Substituted Piperidine Compounds

ABSTRACT

The present disclosure provides substituted piperidine compounds having Formula (I), and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , B, X, and Z are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to treat a disorder responsive to the blockade of SMYD proteins such as SMYD3 or SMYD2. Compounds of the present disclosure are especially useful for treating cancer.

BACKGROUND OF THE INVENTION Field of the Invention

The present disclosure provides substituted piperidines as SMYD proteininhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methodsof treating conditions and diseases wherein inhibition of SMYD proteinssuch as SMYD3 and SMYD2 provides a benefit.

Background

Epigenetic regulation of gene expression is an important biologicaldeterminant of protein production and cellular differentiation and playsa significant pathogenic role in a number of human diseases. Epigeneticregulation involves heritable modification of genetic material withoutchanging its nucleotide sequence. Typically, epigenetic regulation ismediated by selective and reversible modification (e.g., methylation) ofDNA and proteins (e.g., histones) that control the conformationaltransition between transcriptionally active and inactive states ofchromatin. These covalent modifications can be controlled by enzymessuch as methyltransferases (e.g., SMYD proteins such as SMYD3 andSMYD2), many of which are associated with genetic alterations that cancause human disease, such as proliferative disorders. Thus, there is aneed for the development of small molecules that are capable ofinhibiting the activity of SMYD proteins such as SMYD3 and SMYD2.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides substituted piperidinecompounds represented by any one of Formulae I-X below, and thepharmaceutically acceptable salts and solvates thereof, collectivelyreferred to herein as “Compounds of the Disclosure.”

In another aspect, the present disclosure provides a Compound of theDisclosure and one or more pharmaceutically acceptable carriers.

In another aspect, the present disclosure provides a method ofinhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal,comprising administering to the mammal an effective amount of at leastone Compound of the Disclosure.

In another aspect, the present disclosure provides methods for treatinga disease, disorder, or condition, e.g., cancer, responsive toinhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprisingadministering a therapeutically effective amount of a Compound of theDisclosure.

In another aspect, the present disclosure provides the use of Compoundsof the Disclosure as inhibitors of SMYD3.

In another aspect, the present disclosure provides the use of Compoundsof the Disclosure as inhibitors of SMYD2.

In another aspect, the present disclosure provides the use of Compoundsof the Disclosure as inhibitors of SMYD proteins.

In another aspect, the present disclosure provides a pharmaceuticalcomposition for treating a disease, disorder, or condition responsive toinhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, whereinthe pharmaceutical composition comprises a therapeutically effectiveamount of a Compound of the Disclosure in a mixture with one or morepharmaceutically acceptable carriers.

In another aspect, the present disclosure provides Compounds of theDisclosure for use in treating cancer in a mammal, e.g., breast,cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary,esophageal, lung, and prostate cancer.

In another aspect, the present disclosure provides a Compound of theDisclosure for use in the manufacture of a medicament for treatingcancer in a mammal.

In another aspect, the present disclosure provides kit comprising aCompound of the Disclosure.

Additional embodiments and advantages of the disclosure will be setforth, in part, in the description that follows, and will flow from thedescription, or can be learned by practice of the disclosure. Theembodiments and advantages of the disclosure will be realized andattained by means of the elements and combinations particularly pointedout in the appended claims.

It is to be understood that both the foregoing summary and the followingdetailed description are exemplary and explanatory only, and are notrestrictive of the invention as claimed.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present disclosure is based on the use of Compounds ofthe Disclosure as inhibitors of SMYD proteins. In view of this property,the Compounds of the Disclosure are useful for treating diseases,disorders, or conditions, e.g., cancer, responsive to inhibition of SMYDproteins.

One aspect of the present disclosure is based on the use of Compounds ofthe Disclosure as inhibitors of SMYD3. In view of this property, theCompounds of the Disclosure are useful for treating diseases, disorders,or conditions, e.g., cancer, responsive to inhibition of SMYD3.

One aspect of the present disclosure is based on the use of Compounds ofthe Disclosure as inhibitors of SMYD2. In view of this property, theCompounds of the Disclosure are useful for treating diseases, disorders,or conditions, e.g., cancer, responsive to inhibition of SMYD2.

In one embodiment, Compounds of the Disclosure are compounds havingFormula I:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof,wherein:

B is:

X is selected from the group consisting of —S(═O)₂—, —S(═O)₂N(R⁷)—,—S(═O)₂C(R⁸)(H)—, —C(═O)—, —C(═O)N(R⁷)—, —C(═O)O—, —C(═O)C(R⁸)(H)—, and—S(═O)₂N(R⁷)C(═O)N(R¹¹)—; or X is absent, (i.e., Z forms a bond with thenitrogen atom),

wherein the sulfur atom of —S(═O)₂N(R⁷)—, —S(═O)₂C(R⁸)(H)—, or—S(═O)₂N(R⁷)C(═O)N(R¹¹)— is attached to the nitrogen atom of B, thecarbon atom of —C(═O)N(R⁷)— or —C(═O)O— is attached to the nitrogen atomof B, and the carbonyl carbon atom of —C(═O)C(R⁸)(H)— is attached thenitrogen atom of B;

Z is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl,(dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl,(amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl,(aralkylamino)alkyl, [(cycloalkyl)alkylamino]alkyl,[(heterocyclo)alkylamino]alkyl, alkoxyalkyl, optionally substitutedC₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo,optionally substituted 5- to 14-membered heteroaryl, optionallysubstituted C₃₋₁₂ cycloalkyl, aralkyl, and heteroaralkyl;

R¹ is selected from the group consisting of ethyl, n-propyl, isopropyl,isobutyl, and cyclopropyl;

R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) areeach independently selected from the group consisting of hydrogen, halo,C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionallysubstituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or

R^(2a) and R^(2b) taken together with the carbon atom to which they areattached forma C₃₋₆ cycloalkyl; and R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(3b) taken together with the carbon atom to which they areattached forma C₃₋₆ cycloalkyl; and R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(4a) and R^(4b) taken together with the carbon atom to which they areattached forma C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(5a) and R^(5b) taken together with the carbon atom to which they areattached forma C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), and R^(4b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(2a) and R^(5a) taken together form a C₁₋₄ bridge; and R^(2b), R^(3a),R^(3b), R^(4a), R^(4b), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2a), R^(2b),R^(3b), R^(4a), R^(5a), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(2a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2b), R^(3a),R^(3b), R^(4b), R^(5a), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(5a) taken form a C₁₋₄ bridge; and R^(2a), R^(2b), R^(3b),R^(4a), R^(4b), and R^(5b) are each independently selected from thegroup consisting of hydrogen, halo, and C₁₋₄ alkyl;

R⁶ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

R⁷ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

R⁸ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, amino,alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and—N(R⁹)C(═O)R¹⁰;

R⁹ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

R¹⁰ is selected from the group consisting of (amino)alkyl,(alkylamino)alkyl, and (dialkylamino)alkyl; and

R¹¹ is selected from the group consisting of hydrogen and C₁₋₄ alkyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein R¹ is selected from the group consisting ofethyl and cyclopropyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein Z is selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, fluoroalkyl, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl,(heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl,(hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionallysubstituted C₆₋₁₄ aryl, optionally substituted 4- to 14-memberedheterocyclo, optionally substituted 5- to 14-membered heteroaryl,optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and heteroaralkyl,when X is absent.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R⁶ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; andR¹, X, and Z are as defined above in connection with Formula I. Inanother embodiment, R⁶ is selected from the group consisting of hydrogenand methyl. In another embodiment, R⁶ is hydrogen.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(2a) is selected from the group consisting of halo, C₁₋₆ alkyl, C₃₋₁₂cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl,aralkyl, and alkoxycarbonyl; and R¹, X, and Z are as defined above inconnection with Formula I. In another embodiment, B is selected from thegroup consisting of:

In another embodiment, R^(2a) is selected from the group consisting ofmethyl, ethyl, phenyl, —CF₃, —CO₂Et, and —CH₂OH. In another embodiment,R^(2a) is —CH₂Ph.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(3a) is selected from the group consisting of halo, C₁₋₆ alkyl, C₃₋₁₂cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl,aralkyl, and alkoxycarbonyl; and R¹, X, and Z are as defined above inconnection with Formula I. In another embodiment, B is selected from thegroup consisting of:

In another embodiment, R^(3a) is selected from the group consisting ofmethyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and —CH₂Ph. Inanother embodiment, R^(3a) is —CH₂Ph.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(2a) and R^(2b) are each independently selected from the groupconsisting of halo and C₁₋₆ alkyl; or R^(2a) and R^(2b) taken togetherwith the carbon atom to which they are attached form a C₃₋₆ cycloalkyl;and R¹, X, and Z are as defined above in connection with Formula I. Inanother embodiment, B is selected from the group consisting of:

and R^(2a) and R^(2b) taken together with the carbon atom to which theyare attached form a C₃₋₆ cycloalkyl. In another embodiment, B isselected from the group consisting of:

In another embodiment, B is selected from the group consisting of:

and R^(2a) and R^(2b) are each independently selected from the groupconsisting of halo and C₁₋₄ alkyl. In another embodiment, R^(2a) andR^(2b) are selected from the group consisting of fluoro and methyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(3a) and R^(3b) are each independently selected from the groupconsisting of halo and C₁₋₆ alkyl; orR^(3a) and R^(3b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R¹, X, and Z are as defined abovein connection with Formula I. In another embodiment, B is selected fromthe group consisting of:

and R^(3a) and R^(3b) taken together with the carbon atom to which theyare attached form a C₃₋₆ cycloalkyl. In another embodiment, B isselected from the group consisting of:

In another embodiment, B is selected from the group consisting of:

and R^(3a) and R^(3b) are each independently selected from the groupconsisting of halo and C₁₋₄ alkyl. In another embodiment, R^(3a) andR^(3b) are selected from the group consisting of fluoro and methyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(3a) and R^(5a) are each independently C₁₋₆ alkyl; or R^(3a) andR^(5a) taken together form a C₁₋₄ bridge; and R¹, X, and Z are asdefined above in connection with Formula I. In another embodiment, B isselected from the group consisting of:

In another embodiment, R^(3a) and R^(5a) are each independently C₁₋₄alkyl. In another embodiment, R^(3a) and R^(5a) are each methyl orethyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

and R¹, X, and Z are as defined above in connection with Formula I. Inanother embodiment, B is selected from the group consisting of:

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(2a) and R^(3a) are each independently C₁₋₆ alkyl; and R¹, X, and Zare as defined above in connection with Formula I. In anotherembodiment, B is:

In another embodiment, R^(2a) and R^(3a) are each independently C₁₋₄alkyl. In another embodiment, R^(2a) and R^(3a) are each methyl orethyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(3a) and R^(4a) are each independently C₁₋₆ alkyl; or R^(3a) andR^(4a) taken together form a C₁₋₄ bridge; and R¹, X, and Z are asdefined above in connection with Formula I. In another embodiment, B is:

In another embodiment, R^(3a) and R^(4a) are each independently C₁₋₄alkyl. In another embodiment, R^(3a) and R^(4a) are each methyl orethyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is selected from the group consisting of:

and R¹, X, and Z are as defined above in connection with Formula I. Inanother embodiment, B is selected from the group consisting of:

In another embodiment, B is selected from the group consisting of:

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein B is:

R^(2a) and R^(5a) are each independently selected from the groupconsisting of C₁₋₆ alkyl and alkoxycarbonyl; or R^(2a) and R^(5a) takentogether form a C₁₋₄ bridge; and R¹, X, and Z are as defined above inconnection with Formula I. In another embodiment, B is:

In another embodiment, R^(2a) and R^(5a) are each independently selectedfrom the group consisting of C₁₋₄ alkyl and alkoxycarbonyl. In anotherembodiment, R^(2a) and R^(5a) are each independently selected from thegroup consisting of methyl and —CO₂Me.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —S(═O)₂— and R¹, B, and Z are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —C(═O)— and R¹, B, and Z are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is absent and R¹, B, and Z are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —S(═O)₂N(H)— and R¹, B, and Z are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —C(═O)N(H)— and R¹, B, and Z are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —C(═O)O— and R¹, B, and Z are as definedabove in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —S(═O)₂CH₂— and R¹, B, and Z are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is —C(═O)CH₂— and R¹, B, and Z are asdefined above in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is selected from the group consisting of:

R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino,alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and—N(R⁹)C(═O)R¹⁰; and R¹, R⁹, R¹⁰, B, and Z are as defined above inconnection with Formula I. In another embodiment, R⁸ is selected fromthe group consisting of —NH₂, —CH₂NH₂, and —N(H)C(═O)R¹⁰.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein X is selected from the group consisting of:

R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino,alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and—N(R⁹)C(═O)R¹⁰; and R¹, R⁹, R¹⁰, B, and Z are as defined above inconnection with Formula I. In another embodiment, R⁸ is selected fromthe group consisting of —NH₂, —CH₂NH₂, and —N(H)C(═O)R¹⁰.

In another embodiment, Compounds of the Disclosure are compounds havingFormula I, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein Z is selected from the group consisting of(amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C₆₋₁₄aryl, optionally substituted 4- to 14-membered heterocyclo, optionallysubstituted 5- to 14-membered heteroaryl, and optionally substitutedC₃₋₁₂ cycloalkyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula II:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein

R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) areeach independently selected from the group consisting of hydrogen, halo,C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionallysubstituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or

R^(2a) and R^(2b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(3b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(3b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(4a) and R^(4b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(5a) and R^(5b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), and R^(4b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(2a) and R^(5a) taken together form a C₁₋₄ bridge; and R^(2b), R^(3a),R^(3b), R^(4a), R^(4b), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2a), R^(2b),R^(3b), R^(4a), R^(5a), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(2a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2b), R^(3a),R^(3b), R^(4b), R^(5a), and R^(5b) are each independently selected fromthe group consisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(5a) taken form a C₁₋₄ bridge; and R^(2a), R^(2b), R^(3b),R^(4a), R^(4b), and R^(5b) are each independently selected from thegroup consisting of hydrogen, halo, and C₁₋₄ alkyl;

R⁶ is selected from the group consisting of hydrogen and C₁₋₄ alkyl;

with the proviso that a) one or more of R^(2a), R^(3a), R^(4a), andR^(5a) is independently selected from the group consisting of halo, C₁₋₆alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substitutedC₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or b) R⁶ is C₁₋₄ alkyl; and

R¹, X, and Z are as defined in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula II, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein Z is selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, fluoroalkyl, (amino)alkyl,(alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl,(heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl,(hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionallysubstituted C₆₋₁₄ aryl, optionally substituted 4- to 14-memberedheterocyclo, optionally substituted 5- to 14-membered heteroaryl,optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and heteroaralkyl,when X is absent.

In another embodiment, Compounds of the Disclosure are compounds havingFormula II, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, wherein

R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) areeach independently selected from the group consisting of hydrogen, halo,C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionallysubstituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or

R^(2a) and R^(2b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(3a), R^(3b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(3a) and R^(3b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(4a), R^(4b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(4a) and R^(4b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b),R^(5a), and R^(5b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; or

R^(5a) and R^(5b) taken together with the carbon atom to which they areattached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), and R^(4b) are each independently selected from the groupconsisting of hydrogen, halo, and C₁₋₄ alkyl; and

R¹, R⁶, X, and Z are as defined in connection with Formula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula III:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, and optionallysubstituted 4- to 14-membered heterocyclo.

In another embodiment, Compounds of the Disclosure are compounds havingFormula IV:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, and optionallysubstituted 4- to 14-membered heterocyclo.

In another embodiment, Compounds of the Disclosure are compounds havingFormula V:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, optionallysubstituted 4- to 14-membered heterocyclo, and optionally substitutedC₃₋₁₂ cycloalkyl. It will be understood by those of ordinary skill inthe art that compounds having Formula V can be drawn in various ways,e.g.,

In another embodiment, Compounds of the Disclosure are compounds havingFormula VI:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, optionallysubstituted 4- to 14-membered heterocyclo, and optionally substitutedC₃₋₁₂ cycloalkyl. It will be understood by those of ordinary skill inthe art that compounds having Formula VI can be drawn in various ways,e.g.,

In another embodiment, Compounds of the Disclosure are compounds havingFormula VII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, optionallysubstituted 4- to 14-membered heterocyclo, and optionally substitutedC₃₋₁₂ cycloalkyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula VIII:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I. In another embodiment, Z is selected from the groupconsisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, optionallysubstituted 4- to 14-membered heterocyclo, and optionally substitutedC₃₋₁₂ cycloalkyl.

In another embodiment, Compounds of the Disclosure are compounds havingFormula IX:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I.

In another embodiment, Compounds of the Disclosure are compounds havingFormula X:

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof, wherein Z and R¹ are as defined above in connection withFormula I.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is ethyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is ethyl and Z is selectedfrom the group consisting of (heterocyclo)alkyl,(amino)alkyl-substituted phenyl, amino-substituted piperidine,alkylamino-substituted piperidine, dialkylamino-substituted piperidine,and amino-substituted cyclohexyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is n-propyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is n-propyl and Z isselected from the group consisting of (heterocyclo)alkyl,(amino)alkyl-substituted phenyl, amino-substituted piperidine,alkylamino-substituted piperidine, dialkylamino-substituted piperidine,and amino-substituted cyclohexyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is isopropyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is isopropyl and Z isselected from the group consisting of (heterocyclo)alkyl,(amino)alkyl-substituted phenyl, amino-substituted piperidine,alkylamino-substituted piperidine, dialkylamino-substituted piperidine,and amino-substituted cyclohexyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is isobutyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is isobutyl and Z isselected from the group consisting of (heterocyclo)alkyl,(amino)alkyl-substituted phenyl, amino-substituted piperidine,alkylamino-substituted piperidine, dialkylamino-substituted piperidine,and amino-substituted cyclohexyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is cyclopropyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is cyclopropyl and Z isselected from the group consisting of (heterocyclo)alkyl,(amino)alkyl-substituted phenyl, amino-substituted piperidine,alkylamino-substituted piperidine, dialkylamino-substituted piperidine,and amino-substituted cyclohexyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein Z is (heterocyclo)alkyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein Z is a (heterocyclo)alkylhaving the following structure:

wherein R¹² is selected from the group consisting of hydrogen,fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl,aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl,hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl. Inanother embodiment, R¹² is selected from the group consisting ofhydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, and (heteroaryl)alkyl.

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein Z is selected from the groupconsisting of:

In another embodiment, Compounds of the Disclosure are compounds havingany one of Formulae I-X, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, wherein R¹ is cyclopropyl and Z isselected from the group consisting of:

In another embodiment, Compounds of the Disclosure are compounds ofTable 1, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, or a different pharmaceutically acceptable saltthereof. The chemical names of the compounds of Table 1 are provided inTable 1A.

In another embodiment, Compounds of the Disclosure are compounds ofTable 2, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, or a different pharmaceutically acceptable saltthereof. The chemical names of the compounds of Table 2 are provided inTable 2A.

In another embodiment, Compounds of the Disclosure are compounds ofTable 3, and the pharmaceutically acceptable salts or solvates, e.g.,hydrates, thereof, or a different pharmaceutically acceptable saltthereof. The chemical names of the compounds of Table 3 are provided inTable 3A.

In another embodiment, Compounds of the Disclosure are compounds ofTables 1 and 2, and the pharmaceutically acceptable salts or solvates,e.g., hydrates, thereof, or a different pharmaceutically acceptable saltthereof.

In another embodiment, Compounds of the Disclosure are compounds ofTables 1, 2, and 3, and the pharmaceutically acceptable salts orsolvates, e.g., hydrates, thereof, or a different pharmaceuticallyacceptable salt thereof.

In another embodiment, Compounds of the Disclosure are compounds ofTables 1, 1A, 2, 2A, 3, and 3A, and the pharmaceutically acceptablesalts or solvates, e.g., hydrates, thereof, or a differentpharmaceutically acceptable salt thereof.

In another embodiment, Compounds of the Disclosure are selected from thegroup consisting of:

-   N-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((2S,4S)-1-((4-aminopiperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((2S,4S)-1-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((1R,3r,5S)-8-((4-aminopiperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;-   5-cyclopropyl-N-((1R,3r,5S)-8-(((1-(4,4,4-trifluorobutyl)piperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide;    and-   N-((1R,3r,5S)-8-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide,

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof.

In another embodiment, Compounds of the Disclosure are selected from thegroup consisting of:

-   N-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((2S,4S)-1-((4-aminopiperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((2S,4S)-1-((4-(2-aminopropan-2-yl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide;-   N-((1R,3r,5S)-8-((4-aminopiperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide;    and-   5-cyclopropyl-N-((1R,3r,5S)-8-(((1-methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide,

and the pharmaceutically acceptable salts or solvates, e.g., hydrates,thereof.

It should be appreciated that the Compounds of the Disclosure in certainembodiments are the free base, various salts, and hydrate forms, and arenot limited to the particular salt listed in Table 1, Table 2, or Table3.

TABLE 1 Cpd. Salt No. Structure Form  1

HCl  2

HCl  3

TFA  4

TFA  5

TFA  6

HCl  7

HCl  8

TFA  9

TFA  10

HCl  11

HCl  12

TFA  13

HCl  14

HCl  15

HCl  16

None  17

HCl  18

None  19

None  20

None  21

HCl  24

HCl  25

HCl  26

HCl  27

None  28

None  29

None  30

None  31

None  32

HCl  33

HCl  34

HCl  35

HCl  36

HCl  37

HCl  38

HCl  39

HCl  40

HCl  41

None  42

HCl  43

HCl  44

HCl  45

HCl  46

None  47

HCl  48

HCl  49

None  50

None  51

None  52

HCl  53

HCl  54

HCl  55

HCl  56

HCl  57

HCl  58

HCl  59

HCl 11 60

HCl  61

None  62

None  63

HCl  64

None  65

None  66

None  67

None  68

None  69

None  70

None  71

HCl  72

HCl  73

HCl  74

None  75

None  76

HCl  77

HCl  78

HCl  79

HCl  80

HCl  81

HCl  82

HCl  83

HCl  84

None  85

None  86

None  87

HCl  88

HCl  89

HCl  90

None  91

None  92

HCl  93

HCl  94

None  95

HCl  96

HCl  97

HCl  98

HCl  99

None 100

None 101

None 102

None 103

HCl 104

None 105

None 106

HCl 107

None 108

TFA 109

TFA 110

None 111

HCl 112

HCl 113

HCl 114

HCl 115

HCl 116

HCl 117

HCl 118

HCl 119

TFA 120

TFA 121

HCl 122

None 123

HCl 124

None 125

HCl 126

HCl 127

HCl 128

HCl 129

HCl 130

HCl 131

HCl 132

HCl 133

None 134

None 135

HCl 136

HCl 137

None 138

HCl 139

HCl 140

None 141

None 142

HCl 143

HCl 144

None 145

HCl 146

TFA 147

TFA 148

TFA 149

TFA 150

None 151

TFA 152

TFA 153

TFA 154

TFA 155

TFA 156

TFA 157

TFA 158

TFA 159

TFA 160

TFA 161

TFA 162

HCl 163

HCl 164

HCl 165

HCl 166

HCl 167

HCl 168

HCl 169

HCl 170

HCl 171

HCl 172

HCl 173

HCl 174

HCl 175

HCl 176

HCl 177

HCl 178

TFA 179

TFA 180

HCl 181

HCl 182

TFA 183

HCl 184

HCl 185

None 186

None 187

HCl 188

HCl 189

HCl 190

HCl 191

TFA 192

TFA 193

TFA 194

TFA 195

TFA 196

TFA 197

TFA 198

TFA 199

HCl 201

None 202

TFA 203

None 204

HCl 205

HCl 206

HCl 207

HCl 208

HCl 209

HCl 210

None 211

HCl 212

HCl 213

None 214

None 215

None 216

None 217

None 218

TFA 219

TFA 220

TFA 221

TFA 222

TFA 223

None 224

HCl 225

HCl 226

HCl 227

None 228

HCl 229

None 230

None 231

None 232

None 233

None 234

HCl 235

HCl 236

HCl 237

HCl 238

None 239

None 240

None 241

None 242

None 243

None 244

None 245

None 246

None 247

None 248

None 249

None 250

None 251

None 252

None 253

None 254

None 255

None 256

None 257

None 258

HCl 259

HCl 260

None 261

None 262

None 263

None 264

HCl 265

HCl 266

TFA 267

HCl 268

HCl 269

None 270

None 271

None 272

None 273

HCl 274

None 275

None 276

None 277

None 278

None 279

None 280

None 281

HCl 282

None 283

None 284

HCl 285

None 286

None 287

None 288

None 289

None 290

None 291

None 292

HCl 293

TFA 294

HCl 295

HCl 296

None 297

TFA 298

TFA 299

TFA 300

TFA 301

TFA 302

TFA 303

TFA 304

TFA 305

HCl 306

HCl 307

HCl 308

HCl 309

HCl 310

HCl 311

HCl 312

HCl 313

HCl 314

HCl 315

None 316

None 317

HCl 318

None 319

HCl 320

None 321

None 322

None 323

None 324

None 325

None 326

HCl 327

None 328

None 329

HCl 330

None 331

TFA 332

TFA 333

HCl 334

HCl 335

HCl 336

HCl 337

TFA 338

TFA 339

HCl 340

None 341

HCl 342

HCl 343

HCl 344

None 345

None 346

None 347

None 348

HCl 349

HCl 350

None 351

None 352

None 353

None 354

None 355

None 356

TFA 357

HCl 358

HCl 359

HCl 360

None 361

None 362

None 363

TFA 364

HCl 365

HCl 366

HCl 367

HCl 368

HCl 369

HCl 370

HCl 371

HCl 372

HCl 373

HCl 374

None 375

HCl 376

HCl 377

None 378

None 379

None 380

None 381

None 382

HCl 383

None 384

TFA 385

None 386

None 387

None 388

None 389

HCl 390

HCl 391

TFA 392

HCl 393

HCl 394

None 395

None 396

HCl 397

None 398

None 399

None 400

HCl 401

None 402

None 403

None 404

None 405

HCl 406

None 407

None 408

None 409

None 410

None 411

None 412

None 413

None 414

None 415

None 416

None 417

None 418

None 419

None 420

None 421

HCl 422

HCl 423

HCl 424

HCl 425

HCl 426

None 427

None 428

None 429

None 430

None 431

None 432

None 433

None 434

None 435

None 436

None 437

HCl 438

TFA 439

TFA 440

None 441

None 442

None 443

None 444

None 445

HCl 446

None 447

None 448

None 449

None 450

None 451

None 452

None 453

None 454

None 455

None 456

None 457

None 458

None 459

None 460

None 461

HCl 462

HCl 463

HCl 464

None 465

None 466

None 467

None 468

TFA 469

None 470

TFA 471

TFA 472

None 473

None 474

None 475

None 476

None 477

None 478

None 479

HCl 480

None 481

None 482

None 483

None 484

None 485

None 486

None 487

None 488

TFA 489

None 490

None 491

None 492

None 493

None 494

None 495

None 496

None 497

HCl 498

HCl 499

None 500

None 501

HCl 502

HCl 503

HCl 504

None 505

None 506

HCl 507

HCl 508

HCl 509

None 510

None 511

None 512

HCl 513

None 514

None 515

None 516

None 517

None 518

None 519

None 520

HCl 521

None 522

HCl 523

HCl 524

None 525

None 526

None 527

HCl

TABLE 2 Cpd. Salt No. Structure Form 528

None 529

TFA 530

None 531

None 532

TFA 533

None 534

None 535

None 536

HCl 537

None 538

None 539

None 540

None 541

None 542

None 543

None 544

None 545

TFA 546

None 547

None 548

None 549

HCl 550

None 551

None 552

TFA 553

None 554

None 555

None 556

HCl 557

None 558

HCl 559

TFA 560

HCl 561

None 562

None 563

HCl 564

TFA 565

None 566

None 567

TFA 568

None 569

None 570

None 571

HCl 572

None 573

None 574

None 575

None 576

None 577

None 578

None 579

None 580

TFA 581

HCl 582

HCl 583

None 584

None 585

None 586

HCl 587

None 588

None 589

None 590

None 591

None 592

None 593

None 594

TFA 595

None 596

None 597

HCl 598

TFA 599

None 600

HCl 601

TFA 602

HCl 603

TFA 604

HCl 605

None 606

None 607

None 608

None 609

None 610

TFA 611

None 612

None 613

HCl 614

None 615

None 616

HCl 617

HCl 618

HCl 619

HCl 620

None 621

HCl 622

HCl 623

None 624

None 625

None 626

None 627

None 628

TFA 629

None 630

None 631

None 632

None 633

None 634

None 635

None 636

HCl 637

None 638

HCl 639

None 640

None 641

HCl 642

None 643

None 644

None 645

None 646

TFA 647

None 648

None 649

None 650

TFA 651

None 652

HCl 653

HCl 654

None 655

HCl 656

HCl 657

None 658

None 659

None 660

HCl 661

None 662

None 663

None 664

None 665

HCl 666

None 667

HCl 668

HCl 669

None 670

HCl 671

None 672

None 673

HCl 674

HCl 675

None 676

None 677

TFA 678

HCl 679

None 680

None 681

TFA 682

TFA 683

HCl 684

None 685

None 686

None 687

HCl 688

None 689

None 690

None 691

TFA 692

HCl 693

None 694

None 695

TFA 696

HCl 697

None 698

HCl 699

None 700

None 701

HCl 702

HCl 703

None 704

TFA 705

None 706

None 707

None 708

None 709

None 710

None 711

None 712

None 713

HCl 714

HCl 715

HCl 716

HCl 717

None 718

HCl 719

HCl 720

TFA 721

None 722

TFA 723

TFA 724

None 725

None 726

None 727

None 728

None 729

None 730

HCl 731

None 732

None 733

None 734

HCl 735

None 736

None 737

None 738

HCl 739

None 740

HCl 741

None 742

None 743

None 744

None 745

None 746

None 747

None 748

None 749

HCl 750

TFA 751

None 752

None 753

None 754

None 755

None 756

HCl 757

HCl 758

HCl 759

None 760

TFA 761

None 762

None 763

None 764

HCl 765

HCl 766

None

TABLE 3 Cpd. Salt No. Structure Form 767

TFA 768

TFA 769

TFA 770

None 771

TFA 772

None 773

None 774

None 775

HCl 776

None 777

HCl 778

TFA 779

None 780

None 781

None 782

TFA 783

None 784

None 785

None 786

None 787

TFA 788

HCl 789

None 790

TFA 791

None 792

None 793

None 794

None 795

None 796

TFA 797

None 798

None 799

None 800

TFA 801

HCl 802

None 803

None 804

TFA 805

None 806

HCl 807

TFA 808

None 809

TFA 810

None 811

HCl 812

None 813

TFA 814

None 815

None 816

None 817

HCl 818

TFA 819

None 820

None 821

None 822

None 823

None 824

TFA 825

None 826

None 827

None 828

None 829

HCl 830

HCl 831

HCl 832

TFA 833

HCl 834

None 835

TFA 836

None 837

None 838

None 839

None 840

HCl 841

None 842

HCl 843

HCl 844

None 845

None 846

None 847

None 848

None 849

TFA 850

None 851

None 852

TFA 853

None 854

HCl 855

TFA 856

HCl 857

HCl 858

None 859

None 860

None 861

None 862

TFA 863

None 864

None 865

HCl 866

None 867

None 868

HCl 869

None 870

None 871

HCl 872

None 873

None 874

HCl 875

HCl 876

None 877

HCl 878

None 879

HCl 880

None 881

None 882

HCl 883

None 884

HCl 885

None 886

HCl 887

HCl 888

None 889

None 890

None 891

HCl 892

None 893

None 894

None 895

TFA 896

None 897

HCl 898

None 899

None 900

None 901

HCl 902

None 903

None 904

None 905

None 906

None 907

HCl 908

None 910

HCl 911

HCl 912

None 913

HCl 914

None 915

HCl 916

TFA 917

None 918

None 919

None 920

None 921

None 922

None 923

None 924

None 925

HCl 926

None 927

None 928

HCl 929

None 930

None 931

None 932

HCl 933

TFA 934

None 935

None 936

None 937

None 938

None 939

HCl 940

None 941

None 942

HCl 943

None 944

None 945

HCl 946

None 947

None 948

None 949

HCl 950

HCl 951

TFA 952

None 953

HCl 954

HCl 955

None 956

None 957

None 958

None 959

HCl 960

None 961

None 962

None 963

None 964

None 965

HCl 966

None 967

None 968

HCl 969

None 970

HCl 971

None 972

None 973

None 974

None 975

None 976

None 977

TFA 978

None 979

None 980

None 981

None 982

TFA 983

None 984

None 985

None 986

None 987

None 988

HCl 989

HCl 990

None 991

HCl 992

None 993

HCl

TABLE 1A LCMS SMYD3 SMYD3 M + H Biochem Cell Cpd. or IC₅₀ IC₅₀ No.Chemical Name (M + Na) (μM)* (μM)* 1N-(1-(L-phenylalanyl)piperidin-4-yl)-5- 383.5 2.87638cyclopropylisoxazole-3-carboxamide 2N-(1-(D-tryptophyl)piperidin-4-yl)-5- 422.2 15.46877cyclopropylisoxazole-3-carboxamide 3 N-(1-(L-tyrosyl)piperidin-4-yl)-5-399.2 0.48617 cyclopropylisoxazole-3-carboxamide 45-cyclopropyl-N-(1-(glycyl-L- 479.4 0.94728tryptophyl)piperidin-4-yl)isoxazole-3- carboxamide 5(S)-N-(1-(2-amino-3-(4-hydroxy-3- 525.2 0.11601 0.80851iodophenyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6N-((2R)-1-(L-tyrosyl)-2-methylpiperidin-  413.15 2.96934-yl)-5-cyclopropylisoxazole-3- carboxamide 7N-((2S)-1-(L-tyrosyl)-2-methylpiperidin- 413.1 1.044994-yl)-5-cyclopropylisoxazole-3- carboxamide 85-cyclopropyl-N-(1-(Na,1-dimethyl-L- 450.4 1.19566tryptophyl)piperidin-4-yl)isoxazole-3- carboxamide 9(S)-N-(1-(2-amino-3-(3-bromo-4-  477.15 0.21411hydroxyphenyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 10 (R)-N-(1-(3-amino-2- 397.10.31912 1.81743 benzylpropanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 11 (S)-N-(1-(3-amino-2- 397.1 2.41085benzylpropanoyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 12N-(1-(4-benzylpiperidine-4- 438.2 1.59927 carbonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 13N-(1-((1r,4R)-4-aminocyclohexane-1- 361.1 1.29457carbonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 14(S)-N-(1-(2-amino-3-(4- 385.1 4.59243hydroxyphenyl)propyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 15 5-cyclopropyl-N-(1-(piperidine-4-347.1 8.54547 carbonyl)piperidin-4-yl)isoxazole-3- carboxamide 165-cyclopropyl-N-(1-(1-methylpiperidine- 361.1 10.042244-carbonyl)piperidin-4-yl)isoxazole-3- carboxamide 175-cyclopropyl-N-(1-(2-(piperidin-4- 361.1 1.05672yl)acetyl)piperidin-4-yl)isoxazole-3- carboxamide 185-cyclopropyl-N-(1-(2-(1-methylpiperidin- 375.1 5.079984-yl)acetyl)piperidin-4-yl)isoxazole-3- carboxamide 19(R)-N-(1-(2-benzyl-3- 398.1 30.89904 hydroxypropanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 20N-(1-((1r,3r)-3-aminocyclobutane-1-  333.15 5.77474carbonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 21N-(1-((1s,3s)-3-aminocyclobutane-1- 333.1 5.69337carbonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 24N-((3S)-1-((1r,4S)-4-aminocyclohexane-1- 375   1.99675carbonyl)-3-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide25 N-((3R)-1-((1r,4R)-4-aminocyclohexane- 375   0.298881-carbonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 26 (R)-N-(1-(3-amino-2-(4- 413.25.2367 hydroxybenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 27 (S)-N-(1-(3-amino-2-(4- 413.20.34237 hydroxybenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 28(R)-N-(1-(3-amino-2-(4-hydroxy-3-  539.05 2.04271iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 29 (S)-N-(1-(3-amino-2-(4-hydroxy-3- 539.05 0.04225 1.10146 iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 30(R)-5-cyclopropyl-N-(1-(2-hydroxy-3-(4-  386.15 42.67345hydroxyphenyl)propyl)piperidin-4- yl)isoxazole-3-carboxamide 31(R)-5-cyclopropyl-N-(1-(3-hydroxy-2-(4- 540   5.09573 hydroxy-3-iodobenzyl)propanoyl)piperidin-4- yl)isoxazole-3-carboxamide 32N-(1-((R)-3-((S)-3-aminobutanamido)-2- 624   4.11464 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 33N-(1-((S)-3-((S)-3-aminobutanamido)-2- 624   0.47322 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 34(R)-N-(1-(3-(3-aminopropanamido)-2-(4- 610.1 1.63668 hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 35(S)-N-(1-(3-(3-aminopropanamido)-2-(4- 610.1 0.11659 hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 36(R)-N-(1-(3-(2-aminoacetamido)-2-(4-  596.05 9.41289 hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 37(S)-N-(1-(3-(2-aminoacetamido)-2-(4-  596.05 0.62263 hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 38 (R)-N-(1-(3-amino-2-(3-hydroxy-4- 427.15 0.518 methylbenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 39 (S)-N-(1-(3-amino-2-(3-hydroxy-4- 427.15 13.98028 methylbenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 40N-(1-(3-aminopropyl)piperidin-4-yl)-5-  293.05 3.1591cyclopropylisoxazole-3-carboxamide 41 5-cyclopropyl-N-(1- 328   13.88514(ethylsulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 42N-(1-((R)-3-((R)-2-aminopropanamido)-2- 610.1 8.39137 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 43N-(1-((S)-3-((R)-2-aminopropanamido)-2- 610.1 1.23321 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 44N-(1-((R)-3-((R)-3-aminobutanamido)-2-  624.05 13.80215 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 45N-(1-((S)-3-((R)-3-aminobutanamido)-2-  624.05 0.47931 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 46 N-(1-((3-aminopropyl)sulfonyl)-3-371.1 0.11881 1.0204 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 47N-((3S)-1-(D-tyrosyl)-3-methylpiperidin- 413.1 14.881124-yl)-5-cyclopropylisoxazole-3- carboxamide 48N-((3R)-1-(D-tyrosyl)-3-methylpiperidin- 413.1 14.918484-yl)-5-cyclopropylisoxazole-3- carboxamide 495-cyclopropyl-N-((3S)-1-glycyl-3- 307   37.18839methylpiperidin-4-yl)isoxazole-3- carboxamide 505-cyclopropyl-N-((3R,4R)-1-glycyl-3- 307   9.72067methylpiperidin-4-yl)isoxazole-3- carboxamide 515-cyclopropyl-N-((3R,4S)-1-glycyl-3- 307   12.73254methylpiperidin-4-yl)isoxazole-3- carboxamide 525-cyclopropyl-N-((2S)-1-glycyl-2- 307.1 32.52331methylpiperidin-4-yl)isoxazole-3- carboxamide 535-cyclopropyl-N-((2R,4S)-2-methyl-1-(2- 375.1 0.86212(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 545-cyclopropyl-N-((2S,4S)-2-methyl-1-(2- 375.1 2.0772(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 555-cyclopropyl-N-((2R,4R)-2-methyl-1-(2- 375.1 0.6809(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 565-cyclopropyl-N-((2S,4R)-2-methyl-1-(2- 375.1 0.17163 3.18391(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 57N-((2R,4R)-1-((1r,4R)-4-  375.15 0.07164 0.94669aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 58 N-((2R,4S)-1-((1r,4R)-4- (397.2)1.40209 aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 59 N-((2S,4S)-1-((1r,4S)-4-  (397.15)7.96967 aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 60 N-((2S,4R)-1-((1r,4S)-4- 375.11.40665 aminocyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 61N-(1-((R)-3-((S)-2-aminopropanamido)-2- 610.1 15.29772 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 62N-(1-((S)-3-((S)-2-aminopropanamido)-2- 610.1 1.32539 (4-hydroxy-3-iodobenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 63 (R)-N-(1-(3-amino-2-(3-chloro-4- 447.15 0.13855 1.44404 hydroxybenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 64 (S)-N-(1-(3-amino-2-(3-chloro-4-447.1 7.15928 hydroxybenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 65N-((3R)-1-((2-aminoethyl)sulfonyl)-3- 357.1 0.20506 1.05134methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 66N-((3S)-1-((2-aminoethyl)sulfonyl)-3- 357.1 0.59032 3.71821methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 67N-((3S)-1-(L-tyrosyl)-3-methylpiperidin- 413.1 2.323624-yl)-5-cyclopropylisoxazole-3- carboxamide 68N-((3R)-1-(L-tyrosyl)-3-methylpiperidin- 413.1 1.687724-yl)-5-cyclopropylisoxazole-3- carboxamide 695-cyclopropyl-N-((2S)-2-methyl-1-(3-  375.15 12.43914(pyrrolidin-1-yl)propanoyl)piperidin-4- yl)isoxazole-3-carboxamide 705-cyclopropyl-N-((2R)-2-methyl-1-(3- 375.1 7.72648(pyrrolidin-1-yl)propanoyl)piperidin-4- yl)isoxazole-3-carboxamide 71N-((2S)-1-((1s,3R)-3-aminocyclobutane-1- 347.1 2.54308carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide72 N-((2S)-1-((1r,3S)-3-aminocyclobutane-1- 347.1 2.72053carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide73 N-(9-((1r,4r)-4-aminocyclohexane-1- 401.1 5.34634carbonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 745-cyclopropyl-N-((2S)-1-(ethylsulfonyl)- (362)   1.414762-methylpiperidin-4-yl)isoxazole-3- carboxamide 755-cyclopropyl-N-((2R)-1-(ethylsulfonyl)- 342.1 7.307142-methylpiperidin-4-yl)isoxazole-3- carboxamide 765-cyclopropyl-N-((3S,4S)-3-ethyl-1-(2- 389.3 0.54092(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 77N-((2R)-1-((2-aminoethyl)sulfonyl)-2- 357.1 0.63328 2.90646methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 78N-((2S)-1-((2-aminoethyl)sulfonyl)-2-  357.05 0.15511 0.79154methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 79(R)-N-(1-(2-amino-3-(4- 385.1 20.42345hydroxyphenyl)propyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 80 N-(1-(3-aminopropanoyl)-3- 321.16.81137 methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 815-cyclopropyl-N-((2R)-1-glycyl-2- 307.1 22.11145methylpiperidin-4-yl)isoxazole-3- carboxamide 82N-((2S,4S)-1-(3-aminopropanoyl)-2- 321.1 10.50574methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 83N-((2S,4R)-1-(3-aminopropanoyl)-2- 321.1 6.59727methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 84N-((2R)-1-(3-aminopropanoyl)-2- 321.1 6.14386 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 85N-((2S)-1-((1R,3R)-3-aminocyclopentane- 361.2 2.368311-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 86N-((2S)-1-((1R,3S)-3-aminocyclopentane- 361.2 2.563751-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 87N-((2R)-1-((1s,3S)-3-aminocyclobutane-1- 347.1 3.25213carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide88 N-(2-((1r,4r)-4-aminocyclohexane-1- 387   0.15617 2.49959carbonyl)-2-azabicyclo[2.2.2]octan-5-yl)-5-cyclopropylisoxazole-3-carboxamide 89N-(1-((1r,4r)-4-aminocyclohexane-1- 437.1 3.3857carbonyl)-2-phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide90 5-cyclopropyl-N-((2S)-2-methyl-1-  389.15 5.33028((1r,4S)-4-(methylamino)cyclohexane-1-carbonyl)piperidin-4-yl)isoxazole-3- carboxamide 915-cyclopropyl-N-((2S)-2-methyl-1-(2-  376.15 3.91293(piperazin-1-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 925-cyclopropyl-N-((2R)-2-methyl-1-(2-  376.15 0.77789(piperazin-1-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 93N-((3S,4S)-1-(4-aminocyclohexane-1- 389.2 1.61465carbonyl)-3-ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide94 N-((2S)-1-((1r,4S)-4-aminocyclohexane-1- 389.1 2.37948carbonyl)-2-ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide95 N-((2R)-1-((1R,3R)-3-aminocyclopentane-  (383.15) 0.532081-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 96N-((2R)-1-((1R,3S)-3-aminocyclopentane- 361.1 1.899561-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 97N-((2R)-1-((1r,3R)-3-aminocyclobutane-1- 347.1 0.77892carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide98 N-(1-((1r,4r)-4-aminocyclohexane-1- 403.1 0.65544carbonyl)-2-propylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide99 N-(1-((1r,4r)-4-aminocyclohexane-1- 403.1 0.23028 3.05094carbonyl)-2-isopropylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 100N-(5-((1r,4r)-4-aminocyclohexane-1- (423.2) 2.20456carbonyl)-5-azaspiro[3.5]nonan-8-yl)-5-cyclopropylisoxazole-3-carboxamide 101 N-((1R,3S,5S)-8-((1r,4R)-4-(409.2) >10 aminocyclohexane-1-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 102N-((1R,3R,5S)-8-((1r,4R)-4- 387.1 0.10577 1.70139aminocyclohexane-1-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 103 N-((2S)-1-(4-amino-3,3- 363.21.44518 dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 104 N-((2R)-1-(4-amino-3,3-363.2 0.56589 dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1055-cyclopropyl-N-((2S)-1-((1r,4S)-4- 403.1 19.98827(dimethylamino)cyclohexane-1-carbonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 106N-((2S)-1-((1S,3S)-3-aminocyclohexane- 375.1 3.521431-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 107 5-cyclopropyl-N-((2R)-2-methyl-1-361.2 2.51548 (piperidine-3-carbonyl)piperidin-4-yl)isoxazole-3-carboxamide 108 N-(1-((1r,4r)-4-aminocyclohexane-1- 451.31.42279 carbonyl)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 109 N-(2-benzyl-1-(2-(piperidin-4-451.2 0.09677 1.92675 yl)acetyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 110N-((2R)-1-((1r,4R)-4-aminocyclohexane- 389.1 0.09941 0.892931-carbonyl)-2-ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide111 (S)-N-(1-(3-amino-2-(4-hydroxy-3- 481   2.46875(trifluoromethyl)benzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide 112(R)-N-(1-(3-amino-2-(4-hydroxy-3- 455.1 1.09349isopropylbenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 113 N-((2R)-1-(((1r,4R)-4-361.2 4.58751 aminocyclohexyl)methyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 114N-(1-((1r,4r)-4-aminocyclohexane-1- 389.2 1.30613carbonyl)-2,2-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1155-cyclopropyl-N-((2S)-2-methyl-1-(2-(4- 389.2 0.4717methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 1165-cyclopropyl-N-((2R)-2-methyl-1-(2-(4- 389.1 2.9085methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 117N-((2S)-1-((1S,3R)-3-aminocyclohexane-  375.25 5.603351-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 118N-((2R)-1-((2R,5S)-5-aminotetrahydro-  377.25 0.20786 1.351482H-pyran-2-carbonyl)-2-methylpiperidin- 4-yl)-5-cyclopropylisoxazole-3-carboxamide 119 ethyl 4-(5-cyclopropylisoxazole-3- 433.3 2.99148carboxamido)-1-(2-(piperidin-4- yl)acetyl)piperidine-3-carboxylate 120(R)-N-(1-(3-amino-2-(4-hydroxy-3- 481.1 0.08157(trifluoromethyl)benzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide 121(S)-N-(1-(3-amino-2-(4-hydroxy-3- 455.2 0.00957 0.68isopropylbenzyl)propanoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 122N-((2R)-1-(4-aminopiperidine-1- 376.1 0.85107carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide123 N-(2-((1r,4r)-4-aminocyclohexane-1- 373.1 1.16837carbonyl)-2-azabicyclo[2.2.1]heptan-5-yl)-5-cyclopropylisoxazole-3-carboxamide 1245-cyclopropyl-N-((2R)-2-methyl-1- 389   0.27407 2.24358((1r,4R)-4-(methylamino)cyclohexane-1-carbonyl)piperidin-4-yl)isoxazole-3- carboxamide 1255-cyclopropyl-N-(9-(2-(piperidin-4- 401.1 7.75656yl)acetyl)-9-azabicyclo[3.3.1]nonan-3- yl)isoxazole-3-carboxamide 1265-cyclopropyl-N-((1R,3s,5S)-8-(2- 387.1 9.85627(piperidin-4-yl)acetyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 127 5-cyclopropyl-N-((1R,3r,5S)-8-(2- 387.1 1.27842(piperidin-4-yl)acetyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 128 N-((2S)-1-(2-(8-azabicyclo[3.2.1]octan-3-  401.250.84351 yl)acetyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 129N-((2R)-1-(2-(8-azabicyclo[3.2.1]octan-3- 401.1 0.59462yl)acetyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide130 N-((2S)-1-(6-aminospiro[3.3]heptane-2- 387.1 1.30431carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide131 N-((2S)-1-((2R,5S)-5-aminotetrahydro- 377.1 2.081442H-pyran-2-carbonyl)-2-methylpiperidin- 4-yl)-5-cyclopropylisoxazole-3-carboxamide 132 5-cyclopropyl-N-((2S)-2-methyl-1- 361.2 5.54521(piperidine-3-carbonyl)piperidin-4- yl)isoxazole-3-carboxamide 133N-((2S)-1-((R)-5-amino-3- 365.1 6.23726hydroxypentanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 134 N-((2R)-1-((R)-5-amino-3-365.2 1.85646 hydroxypentanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 135 5-cyclopropyl-N-((2R)-1-(5-377.1 2.48647 hydroxypiperidine-3-carbonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 1365-cyclopropyl-N-((2R)-2-methyl-1-(6- 387.1 0.75897azaspiro[2.5]octane-1-carbonyl)piperidin- 4-yl)isoxazole-3-carboxamide137 5-cyclopropyl-N-((2R)-1-((1r,4R)-4-  376.25 41.16974hydroxycyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 138 N-((2S)-1-(((1r,4S)-4- 361.1 4.30775aminocyclohexyl)methyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1395-cyclopropyl-N-((2R)-1-((1r,4R)-4- 403.1 1.6468(dimethylamino)cyclohexane-1-carbonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 1405-cyclopropyl-N-((2R)-2-methyl-1-(2-(3-  389.25 0.84236methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 1415-cyclopropyl-N-((2S)-2-methyl-1-(2-(2-  389.35 3.52551methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 142N-((2S)-1-(4-aminobutanoyl)-2- 335.1 3.64524 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 143N-((2R)-1-((1S,3R)-3-aminocyclohexane- 375.1 1.989911-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1445-cyclopropyl-N-((2R)-2-methyl-1-(6-  387.25 0.54601azaspiro[3.4]octane-2-carbonyl)piperidin- 4-yl)isoxazole-3-carboxamide145 N-(1-((1R,3R)-3-aminocyclopentane-1- 347.1 5.97994carbonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 146N-((3R,4R)-1-((1r,4R)-4- 375.3 2.27591 aminocyclohexane-1-carbonyl)-3-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 1475-cyclopropyl-N-((3R,4R)-3-methyl-1-(2- 375.1 1.52725(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 148N-((3R,4S)-1-((1r,4R)-4- 375.3 0.28218 1.81302aminocyclohexane-1-carbonyl)-3- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1495-cyclopropyl-N-((3R,4S)-3-methyl-1-(2- 375.1 0.29052 3.22445(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 150N-(1-((1r,4r)-4-aminocyclohexane-1- 375.1 0.90972carbonyl)-4-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide151 ethyl 1-((1r,4r)-4-aminocyclohexane-1- 433.3 3.53948carbonyl)-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-3-carboxylate 152N-(1-((1r,4r)-4-aminocyclohexane-1- 397.1 2.2474carbonyl)-3,3-difluoropiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 153 5-cyclopropyl-N-(4-methyl-1-(2-375.3 0.8483 (piperidin-4-yl)acetyl)piperidin-4-yl)isoxazole-3-carboxamide 154 5-cyclopropyl-N-(3,3-difluoro-1-(2- 397.11.55665 (piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide155 N-(1-((1r,4r)-4-aminocyclohexane-1- 389.3 0.57463carbonyl)-3,3-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 156N-(5-((1r,4r)-4-aminocyclohexane-1- 387.2 0.24493 1.75569carbonyl)-5-azaspiro[2.5]octan-8-yl)-5-cyclopropylisoxazole-3-carboxamide 1575-cyclopropyl-N-(3,3-dimethyl-1-(2- 389.3 0.52149(piperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 158N-(1-(4-aminobutanoyl)-4- 335.2 7.3363 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 159 ethyl(2S)-1-(4-aminobutanoyl)-4-(5- 393.2 25.18182 cyclopropylisoxazole-3-carboxamido)piperidine-2-carboxylate 160 ethyl 1-(4-aminobutanoyl)-4-(5-393.2 2.23333 cyclopropylisoxazole-3-carboxamido)piperidine-3-carboxylate 161 N-(1-(4-aminobutanoyl)-3,3-349.3 1.25033 dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 162N-((2S)-1-((1r,4S)-4-aminocyclohexane-1- 437.3 >10carbonyl)-2-phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide163 N-((2R)-1-((1r,4R)-4-aminocyclohexane-  437.25 7.166331-carbonyl)-2-phenylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 1645-cyclopropyl-N-((2R)-2-methyl-1-(2- 403.1 5.90922methyl-2-(piperidin-4- yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 165 5-cyclopropyl-N-((2S)-2-methyl-1-(2- 403.1 4.73168methyl-2-(piperidin-4- yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 166 5-cyclopropyl-N-((2R)-2-methyl-1-(2-(2- 389.1 0.50622methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 1675-cyclopropyl-N-((2R)-1-(2-(4- 391.2 0.91127hydroxypiperidin-4-yl)acetyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 168 5-cyclopropyl-N-((2R)-1-(4- 389.1 3.17831ethylpiperidine-4-carbonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 169 5-cyclopropyl-N-((2S)-1-(4- 389.1 3.77384ethylpiperidine-4-carbonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 170 5-cyclopropyl-N-((2R)-1-(4- 379.1 0.6767fluoropiperidine-4-carbonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 171 N-((2R,4R)-1-(4-aminobutanoyl)-2- 335.1 3.11011methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 172N-((2R,4R)-1-(4-amino-3- 351.1 6.77783hydroxybutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 173N-((2S)-1-(4-amino-3-hydroxybutanoyl)- 351.1 5.263622-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 174N-((2R)-1-((1S,3S)-3-aminocyclohexane- 375.1 0.727661-carbonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 175N-((2R)-1-(6-aminospiro[3.3]heptane-2- 387.1 0.27354 0.98285carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide176 5-cyclopropyl-N-((2S)-2-methyl-1-(3- 375.1 0.62421(pyrrolidin-3-yl)propanoyl)piperidin-4- yl)isoxazole-3-carboxamide 1775-cyclopropyl-N-((2S)-1-(5- 377.2 >10 hydroxypiperidine-3-carbonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 1785-cyclopropyl-N-((2S)-2-methyl-1-(6- 387.1 2.02272azaspiro[3.4]octane-2-carbonyl)piperidin- 4-yl)isoxazole-3-carboxamide179 5-cyclopropyl-N-((2S)-2-methyl-1-(6-  387.25 1.42245azaspiro[2.5]octane-1-carbonyl)piperidin- 4-yl)isoxazole-3-carboxamide180 5-cyclopropyl-N-((2R)-2-methyl-1-(3-  375.25 0.95346(pyrrolidin-3-yl)propanoyl)piperidin-4- yl)isoxazole-3-carboxamide 181N-(9-((3-aminopropyl)sulfonyl)-9- 397   0.09267 0.56598azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 182N-(1-((1R,3S)-3-aminocyclopentane-1- 347.1 4.7946carbonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 183N-(1-((2-aminoethyl)sulfonyl)piperidin-4- 343   1.42123yl)-5-cyclopropylisoxazole-3-carboxamide 184N-((2R,4S)-1-(5-aminopentanoyl)-2- 349.2 2.67277methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 185N-((2R,4S)-1-(benzylsulfonyl)-2-  404.15 4.30641methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 1865-cyclopropyl-N-((2R,4S)-2-methyl-1- 396.1 >10((2,2,2-trifluoroethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide187 N-((2S,4S)-1-((3-aminopropyl)sulfonyl)-2- 371.1 0.00409 0.83104methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 188N-((2S,4R)-1-((3-aminopropyl)sulfonyl)- 371.1 0.072292-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 189N-((2R,4R)-1-((3-aminopropyl)sulfonyl)- 371.1 0.05594 1.241132-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 190N-((3R,4S)-1-((1r,4R)-4- 389.1 0.352 aminocyclohexane-1-carbonyl)-3-ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 191N-(8-((1r,4r)-4-aminocyclohexane-1- 387.2 >10carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 192 ethyl(2S)-1-((1r,4S)-4-aminocyclohexane- 433.1 7.083161-carbonyl)-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-2-carboxylate 193N-((3R,4S)-1-(4-aminobutanoyl)-3- 335.2 2.86619 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 194 N-((3S,4R)-1-(4-aminobutanoyl)-3-335.2 1.36537 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 195 N-((3R,4R)-1-(4-aminobutanoyl)-3-335.2 >10 methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide196 N-((3S,4S)-1-(4-aminobutanoyl)-3- 335.2 6.90946methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 197N-(1-(4-aminobutanoyl)-3,3- 357.1 >10 difluoropiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 198 N-(5-(4-aminobutanoyl)-5- 347.10.82956 azaspiro[2.5]octan-8-yl)-5- cyclopropylisoxazole-3-carboxamide199 N-(8-(4-aminobutanoyl)-8- 347.1 0.67809azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 201N-((2S)-1-(4-aminopiperidine-1- 376.1 2.22535carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide202 N-((2R)-1-(4-aminocubane-1-carbonyl)-2- 395.1 0.14195 1.30843methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 203N-(1-((1r,4r)-4-aminocyclohexane-1-  389.25 0.37891carbonyl)-2,3-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 204 N-((2S)-1-(2-(1-  375.25 4.67985(aminomethyl)cyclobutyl)acetyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 205 N-((2R)-1-(2-(1- 375.1 1.99119(aminomethyl)cyclobutyl)acetyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 2065-cyclopropyl-N-((2S)-2-methyl-1-(2-(3- 389.1 1.58733methylpiperidin-4-yl)acetyl)piperidin-4- yl)isoxazole-3-carboxamide 2075-cyclopropyl-N-((2S)-1-(4- 379.2 2.60074fluoropiperidine-4-carbonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 208 N-((2R,4S)-1-(4-aminobutanoyl)-2- 335.1 3.81793methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 209N-((2R,4S)-1-((3-aminopropyl)sulfonyl)-  371.15 0.10032-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 210N-(1-((3-aminopropyl)sulfonyl)piperidin- 357.1 0.32133 2.901384-yl)-5-cyclopropylisoxazole-3- carboxamide 211N-(9-(4-aminobutanoyl)-9- 361.1 5.85206 azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 212N-((2R,4R)-1-(5-aminopentanoyl)-2-  349.15 0.83765methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 2135-cyclopropyl-N-((2R,4S)-1- 354   >10(cyclopropylsulfonyl)-2-methylpiperidin- 4-yl)isoxazole-3-carboxamide214 5-cyclopropyl-N-((2R,4S)-2-methyl-1-(N- 343   >10methylsulfamoyl)piperidin-4-yl)isoxazole- 3-carboxamide 2155-cyclopropyl-N-((2R,4S)-1-((2- (394.1) >10 methoxyethyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 2165-cyclopropyl-N-((2R,4R)-1- 354   >10(cyclopropylsulfonyl)-2-methylpiperidin- 4-yl)isoxazole-3-carboxamide217 5-cyclopropyl-N-((2R,4R)-2-methyl-1-(N- 343.1 6.75805methylsulfamoyl)piperidin-4-yl)isoxazole- 3-carboxamide 218N-(1-((3-aminopropyl)sulfonyl)-4- 371.2 0.23041 1.4182methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 219N-(1-(4-aminobutanoyl)-2-(tert- 377.2 6.31559 butyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 220 N-((3R,4R)-1-(4-aminobutanoyl)-3-397.2 2.52191 phenylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 221 N-((3R,4S)-1-(4-aminobutanoyl)-3-397.1 >10 phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide222 N-((2S)-1-(4-aminocubane-1-carbonyl)-2- 395.1 4.63995methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 2235-cyclopropyl-N-((2S)-1-(2-(4- 391.1 7.18894hydroxypiperidin-4-yl)acetyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 224 5-cyclopropyl-N-((2R)-2-methyl-1-(4-  375.15 1.41743methylpiperidine-4-carbonyl)piperidin-4- yl)isoxazole-3-carboxamide 225N-((2R,4S)-1-(4-amino-3- 351.1 9.0491hydroxybutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 226N-((2S)-1-(2-(3-aminocyclohexyl)acetyl)- 389.1 2.384262-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 227N-(1-(2-(1H-imidazol-4-yl)acetyl)-2- 358.1 >10 >40methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 228N-((2S,4S)-1-(5-aminopentanoyl)-2-  349.15 1.28279methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 2295-cyclopropyl-N-((2S,4S)-2-methyl-1- 356   0.8625(propylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 2305-cyclopropyl-N-((2S,4S)-1- 370.1 0.47239(isobutylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 231ethyl 2-(((2S,4S)-4-(5- 400.1 1.16807cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)acetate 2325-cyclopropyl-N-((2S,4S)-2-methyl-1- 396.1 3.26173((2,2,2-trifluoroethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide233 5-cyclopropyl-N-((2S,4S)-1-((2- 372   2.36218methoxyethyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3- carboxamide234 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((1- 394   1.2429methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 235 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 418   1.333183.2982 (phenethylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2365-cyclopropyl-N-((2S,4S)-2-methyl-1-  410.05 1.03937((3,3,3-trifluoropropyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide237 5-cyclopropyl-N-((2S,4S)-1-((2- 400   3.46488isopropoxyethyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 238 5-cyclopropyl-N-((2R,4S)-2-methyl-1-  356.05 >10(propylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 2395-cyclopropyl-N-((2R,4S)-1- 370.1 >10(isobutylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 240N-((2R,4S)-1-(butylsulfonyl)-2- 370.1 >10 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 241 N-((2R,4S)-1-((6-chloropyridin-3- 425.05 >10 yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 2425-cyclopropyl-N-((2R,4S)-2-methyl-1-  383.15 >10(pyrrolidin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2435-cyclopropyl-N-((2R,4S)-2-methyl-1-((4-  412.15 1.75762methylpiperazin-1-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide244 N-((2S,4R)-1-(benzylsulfonyl)-2- 404   >10 14.06578methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 245 ethyl2-(((2S,4R)-4-(5- 400.1 >10 cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)acetate 2465-cyclopropyl-N-((2S,4R)-2-methyl-1- 396   >10((2,2,2-trifluoroethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide247 5-cyclopropyl-N-((2S,4R)-1- 354.1 >10(cyclopropylsulfonyl)-2-methylpiperidin- 4-yl)isoxazole-3-carboxamide248 5-cyclopropyl-N-((2S,4R)-1-((2- 372.1 >10 methoxyethyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 2495-cyclopropyl-N-((2R,4R)-2-methyl-1- 356.1 >10(propylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 2505-cyclopropyl-N-((2R,4R)-1-  370.15 9.44683(isobutylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 251N-((2R,4R)-1-(butylsulfonyl)-2- 370.1 6.15252 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 252 ethyl 2-(((2R,4R)-4-(5- 400.05 >10 cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)acetate 253N-((2R,4R)-1-((6-chloropyridin-3- 425.1 >10yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 2545-cyclopropyl-N-((2R,4R)-2-methyl-1-  383.15 4.13805(pyrrolidin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2555-cyclopropyl-N-((2R,4R)-2-methyl-1-((4- 412.1 1.19523methylpiperazin-1-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide256 methyl 3-(((2R,4R)-4-(5- 400.1 >10cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)propanoate 2575-cyclopropyl-N-((2R,4R)-1-((2- 372   9.2914 methoxyethyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 2585-cyclopropyl-N-((2R,4R)-2-methyl-1- 410   8.37154((3,3,3-trifluoropropyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide259 5-cyclopropyl-N-((2R,4R)-1-((3-  386.15 >10methoxypropyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3- carboxamide260 5-cyclopropyl-N-((2S,4S)-1- 341.9 2.44732(ethylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 2615-cyclopropyl-N-((2R,4R)-1- 342   >10(ethylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 2625-cyclopropyl-N-((2S,4R)-1-  342.05 >10(ethylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 263N-(1-((1r,4r)-4-aminocyclohexane-1- 389.2 0.03219 0.56899carbonyl)-2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 264N-((2R)-1-(2-(3-aminocyclohexyl)acetyl)- 389   0.409662-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 265N-(2-(4-aminobutanoyl)-2- 347.1 5.44619 >40azabicyclo[2.2.2]octan-5-yl)-5- cyclopropylisoxazole-3-carboxamide 266N-((2S,4R)-1-(2-(1- 403.1 >10 (aminomethyl)cyclohexyl)acetyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 267N-((2R,4S)-1-(2-(1- 403.1 8.51913 (aminomethyl)cyclohexyl)acetyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 268N-((2R,4S)-1-(4-amino-3,3- 363.1 3.15461dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 269N-((2S,4S)-1-(4-amino-3-benzylbutanoyl)- 425.2 >10 >402-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 270N-((2R,4S)-1-(4-amino-3- 425.2 >10 >40benzylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 271 N-((2S,4R)-1-(4-amino-3-425.2 >10 >40 benzylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 272 N-((2R,4R)-1-(4-amino-3-425.2 >10 >40 benzylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 273N-((2S,4R)-1-(5-aminopentanoyl)-2-  349.15 7.82701methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 274N-((2S,4S)-1-(benzylsulfonyl)-2- (426.1) 0.43325 1.41883methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 2755-cyclopropyl-N-((2S,4S)-2-methyl-1-  391.05 0.1537 0.67609(pyridin-2-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2765-cyclopropyl-N-((2S,4S)-1- 354   3.63356(cyclopropylsulfonyl)-2-methylpiperidin- 4-yl)isoxazole-3-carboxamide277 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 383   0.65372(pyrrolidin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2785-cyclopropyl-N-((2S,4S)-2-methyl-1-(N- 343   2.89251methylsulfamoyl)piperidin-4-yl)isoxazole- 3-carboxamide 2795-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 412   0.08154 0.26586methylpiperazin-1-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide280 methyl 3-(((2S,4S)-4-(5- 400   4.85331cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)propanoate 2815-cyclopropyl-N-((2S,4S)-1-((3- 386   1.86694 methoxypropyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 282 methyl3-(((2R,4S)-4-(5- 400   >10 cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)propanoate 2835-cyclopropyl-N-((2R,4S)-2-methyl-1-((1- 394   >10 >40methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 284 5-cyclopropyl-N-((2R,4S)-1-((3-  386.15 >10methoxypropyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3- carboxamide285 5-cyclopropyl-N-((2R,4S)-1-((2- 400   >10isopropoxyethyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 286 5-cyclopropyl-N-((2S,4R)-2-methyl-1-  391.05 >1010.65927 (pyridin-2-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide287 N-((2S,4R)-1-((6-chloropyridin-3- 425   >10yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 2885-cyclopropyl-N-((2S,4R)-2-methyl-1- 383.1 >10(pyrrolidin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2895-cyclopropyl-N-((2S,4R)-2-methyl-1-(N- 343   >10methylsulfamoyl)piperidin-4-yl)isoxazole- 3-carboxamide 290 methyl3-(((2S,4R)-4-(5- 400   >10 cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)propanoate 2915-cyclopropyl-N-((2S,4R)-2-methyl-1-((1- 394   >10 >40methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 292 5-cyclopropyl-N-((2S,4R)-2-methyl-1- 410   >10((3,3,3-trifluoropropyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide293 5-cyclopropyl-N-((2R,4R)-2-methyl-1-  391.05 4.84236 7.19436(pyridin-2-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2945-cyclopropyl-N-((2R,4R)-2-methyl-1-((1- 394   >10 >40methyl-1H-imidazol-4- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 295 5-cyclopropyl-N-((2R,4R)-2-methyl-1- 418.1 >10 >40(phenethylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 2965-cyclopropyl-N-((2R,4R)-1-((2- 400   5.96704isopropoxyethyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 297 N-((3R,4S)-1-(4-aminobutanoyl)-3- 349.1 1.80484ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 298N-((3R,4R)-1-(4-aminobutanoyl)-3- 349.1 6.09665 ethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 299 N-((3S,4R)-1-(4-aminobutanoyl)-3-349.1 0.98944 ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide300 N-((3S,4S)-1-(4-aminobutanoyl)-3- 349.1 3.60037ethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 301N-(1-(4-aminobutanoyl)-1- 389.2 6.46534 azaspiro[5.5]undecan-4-yl)-5-cyclopropylisoxazole-3-carboxamide 302N-((2S,6R)-1-(4-aminobutanoyl)-2,6- 377.3 6.93186diethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 303N-(1-((1r,4r)-4-aminocyclohexane-1- 389.1 1.78233carbonyl)-3,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 304N-(1-((1r,4r)-4-aminocyclohexane-1- 429.1 2.03567carbonyl)-3-(trifluoromethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3055-cyclopropyl-N-((2R,4R)-2-methyl-1- 389.2 1.16784((S)-2-(piperidin-4-yl)propanoyl)piperidin- 4-yl)isoxazole-3-carboxamide306 5-cyclopropyl-N-((2R,4R)-2-methyl-1- 389.2 0.85247((R)-2-(piperidin-4- yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 307 5-cyclopropyl-N-((2R,4S)-2-methyl-1- 389.1 0.92847((S)-2-(piperidin-4-yl)propanoyl)piperidin- 4-yl)isoxazole-3-carboxamide308 5-cyclopropyl-N-((2R,4S)-2-methyl-1- 389.1 0.17867((R)-2-(piperidin-4- yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 309 N-((2R,4R)-1-((1r,4R)-4- 451.3 1.18016 16.79585aminocyclohexane-1-carbonyl)-2- benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 310 N-((2S,4S)-1-((1r,4S)-4- 451.40.73318 8.10326 aminocyclohexane-1-carbonyl)-2- benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 311 N-((2S,4R)-1-(4-amino-3,3- 363.11.61667 dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 312 N-((2R,4R)-1-(4-amino-3,3-363.1 0.4155 dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 313 N-((2R,4S)-1-(4-amino-3-411.2 5.02398 phenylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 314 N-((2R,4R)-1-(4-amino-3- 411.25 4.72554 >40 phenylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3155-cyclopropyl-N-((2S,4S)-1-(N,N- (379.1) 1.32822 4.84171dimethylsulfamoyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 316N-((2S,4S)-1-(butylsulfonyl)-2- 370.2 0.23719 0.78207methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 3175-cyclopropyl-N-((2S,4S)-2-methyl-1- 391   0.68629 4.10919(pyridin-3-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 318N-((2S,4S)-1-((6-chloropyridin-3- 425.1 1.88386yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3195-cyclopropyl-N-((2S,4S)-2-methyl-1- 405   1.42682 4.52678((pyridin-3-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide320 ethyl 2-(((2R,4S)-4-(5-  400.05 >10cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-yl)sulfonyl)acetate 3215-cyclopropyl-N-((2R,4S)-2-methyl-1- 391   4.46652(pyridin-2-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 3225-cyclopropyl-N-((2S,4R)-2-methyl-1- 356   >10(propylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 3235-cyclopropyl-N-((2S,4R)-1- 370.3 >10(isobutylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 3245-cyclopropyl-N-((2S,4R)-2-methyl-1-((4- 412.2 1.64608methylpiperazin-1-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide325 5-cyclopropyl-N-((2S,4R)-2-methyl-1- 405   >10((pyridin-3-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide326 5-cyclopropyl-N-((2S,4R)-2-methyl-1- 418   >10(phenethylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 3275-cyclopropyl-N-((2S,4R)-1-((3- 386   >10 methoxypropyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 3285-cyclopropyl-N-((2R,4R)-1-(N,N-  357.15 6.91182 15.20884dimethylsulfamoyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 3295-cyclopropyl-N-((2R,4R)-2-methyl-1- 405   6.42224 20.04736((pyridin-3-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide330 N-((2R,4R)-1-((4- 447.2 >10 29.32443 acetamidophenyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 331 ethyl1-((3-aminopropyl)sulfonyl)-4-(5- 429.2 0.14739 2.30591cyclopropylisoxazole-3- carboxamido)piperidine-3-carboxylate 332N-(1-(4-aminobutanoyl)-3,5- 349.2 2.53113 dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 333 N-((2R,4R)-1-(4-aminobutanoyl)-2- 411.25 >10 >40 benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 334 N-((2S,4R)-1-(4-aminobutanoyl)-2- 411.25 1.89516 33.02657 benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 335 N-((2R,4S)-1-(4-aminobutanoyl)-2- 411.25 1.11818 19.61527 benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 336 N-((2S,4S)-1-(4-aminobutanoyl)-2- 411.25 0.05412 1.62405 benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 337 N-((2S,4S)-1-(4-amino-3,3- 363.10.96148 12.99612 dimethylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 338N-((2S,4S)-1-(4-amino-3-phenylbutanoyl)- 411.1 0.84162-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 339N-((2S,4R)-1-(4-amino-3- 411.1 4.66558phenylbutanoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 340N-((2S,4S)-1-(1H-benzo[d]imidazole-5- 394.2 >10 >40carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide341 N-((2R,4R)-1-(1H-benzo[d]imidazole-5- 394.2 1.00187 6.0106carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide342 N-((2R,4R)-1-(3- 389.2 0.55215(aminomethyl)cyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 343 N-((2R,4S)-1-(3-  389.25 1.06666(aminomethyl)cyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3445-cyclopropyl-N-((2R,4S)-2-methyl-1- 418.2 >10(phenethylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 3455-cyclopropyl-N-((2R,4S)-2-methyl-1- 410   >10((3,3,3-trifluoropropyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide346 5-cyclopropyl-N-((2S,4R)-1-(N,N-  357.15 >10dimethylsulfamoyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 347N-((2S,4R)-1-(butylsulfonyl)-2- 370   8.02269 methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 348N-((2S,4S)-2-benzyl-1-(2-(piperidin-4- 451.1 0.02251 0.83834yl)acetyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 349N-((2R,4R)-2-benzyl-1-(2-(piperidin-4- 451.1 2.26536 >40yl)acetyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 3505-cyclopropyl-N-((2R,4S)-1- 451.2 >10(ethylsulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 3515-cyclopropyl-N-((2R,4R)-2-methyl-1- 390   3.09195 7.83322(phenylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 3525-cyclopropyl-N-((2S,4S)-2-methyl-1- 390   0.15159 0.99614(phenylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 3535-cyclopropyl-N-((2R,4S)-2-methyl-1- 390.1 3.97616(phenylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 354N-((2R,4R)-1-((3-cyanophenyl)sulfonyl)-  (437.15) 1.13679 5.652652-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 355N-((2R,4S)-1-((3-cyanophenyl)sulfonyl)- 415   0.277782-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 356N-(1-(4-aminobutanoyl)-3- 389.2 1.21465(trifluoromethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide357 N-((2R)-1-((R)-3-amino-2-(4- 427.1 1.1652hydroxybenzyl)propanoyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3585-cyclopropyl-N-((2S,4R)-2-methyl-1- 389.1 3.39874((S)-2-(piperidin-4-yl)propanoyl)piperidin- 4-yl)isoxazole-3-carboxamide359 5-cyclopropyl-N-((2S,4R)-2-methyl-1- 389.1 1.4568((R)-2-(piperidin-4- yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 360 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 389.1 0.791718.2842 ((S)-2-(piperidin-4-yl)propanoyl)piperidin-4-yl)isoxazole-3-carboxamide 361 5-cyclopropyl-N-((2S,4S)-2-methyl-1-389.1 1.36293 13.61968 ((R)-2-(piperidin-4-yl)propanoyl)piperidin-4-yl)isoxazole-3- carboxamide 3625-cyclopropyl-N-((3S,4R)-3- 391.1 2.95081(hydroxymethyl)-1-(2-(piperidin-4- yl)acetyl)piperidin-4-yl)isoxazole-3-carboxamide 363 N-((2R,4R)-1-((1r,4R)-4- 391.1 1.98513aminocyclohexane-1-carbonyl)-2- (hydroxymethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 364 N-((2R,4S)-1-((1r,4R)-4- 451.24.56731 aminocyclohexane-1-carbonyl)-2- benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 365 N-((2R,4R)-1-(3-(2-aminopropan-2-411.3 0.45355 3.88138 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 366 N-((2S,4R)-1-(3-(2-aminopropan-2- 411.25 2.75278 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 367 N-((2S,4S)-1-(3-(2-aminopropan-2-411.5 4.28845 30.57389 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 368 N-((2R,4R)-1-(4-(2-aminopropan-2-411.3 0.12223 1.0362 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 369 N-((2S,4R)-1-(4-(2-aminopropan-2-(433.1) 5.87044 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 370 N-((2S,4S)-1-(4-(2-aminopropan-2-411.3 4.39381 >40 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 371 N-((2R,4S)-1-(4-(2-aminopropan-2-(433.1) 4.9531 yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 372 N-((2S,4R)-1-(3- 389.2 5.88826(aminomethyl)cyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 373 N-((2S,4S)-1-(3- 389.2 2.4668829.7807 (aminomethyl)cyclohexane-1-carbonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 3745-cyclopropyl-N-((2R,4S)-2-methyl-1- 405   >10((pyridin-3-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide375 N-((2R,4S)-2-benzyl-1-(2-(piperidin-4- 451.3 1.82988yl)acetyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 376N-((2S,4R)-2-benzyl-1-(2-(piperidin-4- 451.3 1.32288yl)acetyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 377N-((2S,4R)-1-((4- 447.1 >10 27.64364 acetamidophenyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 378N-((2S,4S)-1-((4- 447.2 0.57713 2.74476 acetamidophenyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 3795-cyclopropyl-N-((2S,4R)-2-methyl-1- 390   3.35227(phenylsulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 380N-((2S,4R)-1-((3-cyanophenyl)sulfonyl)-  (437.15) 0.323252-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 3815-cyclopropyl-N-((2S,4S)-1-((6- 476.3 >10 >40(isobutyl(methyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 382 N-((3R,4R)-1-((1r,4R)-4- 391.1 2.54424aminocyclohexane-1-carbonyl)-3- (hydroxymethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 383 5-cyclopropyl-N-((3R,4R)-3- 391.43.02223 (hydroxymethyl)-1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)isoxazole-3- carboxamide 384N-((2S,4R)-1-((1r,4S)-4- 391.1 4.03559 aminocyclohexane-1-carbonyl)-2-(hydroxymethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 385N-((3S,4S)-1-((3-aminopropyl)sulfonyl)-3- 371   0.08821 1.22936methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 386N-((3S,4R)-1-((3-aminopropyl)sulfonyl)- 371   0.02816 0.339523-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 387N-((3R,4S)-1-((3-aminopropyl)sulfonyl)-  371.15 0.07 0.787743-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 388N-((3R,4R)-1-((3-aminopropyl)sulfonyl)- 371.2 0.462453-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 389N-((2S,4R)-1-((1r,4S)-4- 451.2 >10 aminocyclohexane-1-carbonyl)-2-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 390N-((2R,4R)-1-((3-aminopropyl)sulfonyl)- 447.2 0.4637 2.971882-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 391N-((2S,4S)-1-(2-(1- 403.2 5.72321 >10 (aminomethyl)cyclohexyl)acetyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 392N-((2R,4S)-1-(3-(2-aminopropan-2- 411.1 >10yl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 393 5-cyclopropyl-N-((2S,4S)-1-((1-386   3.15999 methoxypropan-2-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 3945-cyclopropyl-N-((2S,4R)-1-((2- 400.1 >10 isopropoxyethyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 395N-((1R,3s,5S)-8-((2-aminoethyl)sulfonyl)- 369.1 0.6108 3.16418-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 396N-((1R,3r,5S)-8-((2-aminoethyl)sulfonyl)-  369.15 0.04169 0.37478-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 397N-((2R,4S)-1-((4- 447.1 >10 >10 acetamidophenyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 398N-((2S,4S)-1-((3-cyanophenyl)sulfonyl)-2- 415   0.212 1.2065methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 3995-cyclopropyl-N-((1R,3s,5S)-8- 402   0.83319 2.86872(phenylsulfonyl)-8-azabicyclo[3.2.1]octan- 3-yl)isoxazole-3-carboxamide400 5-cyclopropyl-N-((1R,3r,5S)-8- 402   4.1308 >10(phenylsulfonyl)-8-azabicyclo[3.2.1]octan- 3-yl)isoxazole-3-carboxamide401 5-cyclopropyl-N-(9-(phenylsulfonyl)-9- 416   0.79319 2.94997azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 402N-(9-((4-acetamidophenyl)sulfonyl)-9- 473.1 4.92371 >10azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 403N-((1R,3r,5S)-8-((4- 458.9 10 >10 acetamidophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 4045-cyclopropyl-N-((1R,3s,5S)-8-((2-oxo- 459   1.40067 2.918162,3-dihydrobenzo[d]oxazol-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 4055-cyclopropyl-N-((1R,3r,5S)-8-((2-oxo- 458.9 9.39268 >102,3-dihydrobenzo[d]oxazol-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 406N-((2S,4R)-2-benzyl-1-((2-(pyrrolidin-1-  487.35 3.41263yl)ethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide407 N-((2R,4R)-2-benzyl-1-((2-(pyrrolidin-1- 487.1 3.81295 >10yl)ethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide408 N-((2R,4S)-2-benzyl-1-((2-(pyrrolidin-1- 487.1 1.14883yl)ethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide409 N-((2S,4R)-2-benzyl-1-((2- (525.3) >10morpholinoethyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 410 5-cyclopropyl-N-(9-((3- 467.16.3223 >10 morpholinopropyl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 4115-cyclopropyl-N-((2S,4R)-1-((6- 476.1 >10(isobutyl(methyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 412 5-cyclopropyl-N-((2S,4S)-1-((6-((2- 478.32.12299 8.22448 methoxyethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 4135-cyclopropyl-N-((2S,4S)-1-((6-((2-  464.25 1.4827 4.51041methoxyethyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 414 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((6-533.3 0.88858 2.60848 (methyl(2- morpholinoethyl)amino)pyridin-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 415N-((2S,4R)-1-((6-((2- 449.1 0.13482 5.61852aminoethyl)amino)pyridin-3-yl)sulfonyl)- 2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 416 5-cyclopropyl-N-(8-((piperidin-4-0.16357 ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 417 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 411   0.003070.0508 ((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 418 5-cyclopropyl-N-((2R,4R)-2-methyl-1- 410.95 0.01717 0.19706 ((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 419 N-((2S,4R,5S)-1-((1r,4S)-4-  389.251.95467 >10 aminocyclohexane-1-carbonyl)-2,5- dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 420 N-((2R,4S,5R)-1-((1r,4R)-4- 389.20.01132 0.20488 aminocyclohexane-1-carbonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 421N-((3S,4S)-1-((1r,4S)-4- 391.1 2.51243 aminocyclohexane-1-carbonyl)-3-(hydroxymethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 422N-((3R,4S)-1-((1r,4R)-4- 391.1 1.9415 aminocyclohexane-1-carbonyl)-3-(hydroxymethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 423N-((2R,4S)-1-((3-aminopropyl)sulfonyl)- 447.2 0.25029 1.855542-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 424N-((2S,4S)-1-((3-aminopropyl)sulfonyl)-2- 447.2 0.22763 1.80492benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 425N-((2R,4S)-1-(1H-benzo[d]imidazole-5- 394   >10carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide426 N-((2S,4R)-1-(1H-benzo[d]imidazole-5- 394   >10carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide427 N-(1-(2-(1H-imidazol-2-yl)acetyl)-2- 358.1 >10 >10methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 428N-((2R,4R)-1-((1H-imidazol-4- 380   0.73212 2.58364yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 429 N-((1R,3R,5S)-8-((1s,4S)-4- 387.10.35096 aminocyclohexane-1-carbonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 430 N-((1R,3s,5S)-8-((4- 459.23.65777 4.51957 acetamidophenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 4315-cyclopropyl-N-((1R,3r,5S)-8-((4-  522.25 >10 >10(isonicotinamido)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 432N-((1R,3r,5S)-8-((6-chloro-2-oxoindolin-  491.15 6.29941 >105-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 4335-cyclopropyl-N-((1R,3r,5S)-8-((2- 457   4.19179 >10oxoindolin-5-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 434 5-cyclopropyl-N-((1R,3r,5S)-8-((2-oxo- 458   2.40802 >102,3-dihydro-1H-benzo[d]imidazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 4355-cyclopropyl-N-((1R,3s,5S)-8-((2- 423.2 2.00184 5.58678(pyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 4365-cyclopropyl-N-((1R,3r,5S)-8-((2- 423.2 0.0613 0.28517(pyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 437N-((2S,4S)-2-benzyl-1-((2-(pyrrolidin-1- 487.1 1.00347 4.62346yl)ethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide438 N-((2S,4R)-2-benzyl-1-((3-  517.35 9.17764 >10morpholinopropyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 439 N-((2R,4R)-2-benzyl-1-((3- 517.35 >10 >10 morpholinopropyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 4405-cyclopropyl-N-((1R,3s,5S)-8-((2- 439.2 >10 >10morpholinoethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 441 5-cyclopropyl-N-((1R,3r,5S)-8-((2-  439.25 1.611263.67271 morpholinoethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 4425-cyclopropyl-N-(9-((2-(pyrrolidin-1- 437.1 1.11218 4.5508yl)ethyl)sulfonyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 443 5-cyclopropyl-N-(9-((2- 453   >10 >10morpholinoethyl)sulfonyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 444 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((3- 385   0.013090.18073 (methylamino)propyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 445 N-(5-((3-aminopropyl)sulfonyl)-5- 397  0.13047 azaspiro[3.5]nonan-8-yl)-5- cyclopropylisoxazole-3-carboxamide446 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((6- 420.2 0.89031 2.25375(methylamino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 447 5-cyclopropyl-N-((2R,4S)-2-methyl-1-((6- 420   >10(methylamino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 448 5-cyclopropyl-N-((2S,4R)-2-methyl-1-((6- 420.1 >10(methylamino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 449 5-cyclopropyl-N-((2R,4R)-2-methyl-1-((6- 420   >10 >10(methylamino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 450 5-cyclopropyl-N-((2S,4S)-1-((6- 462.1 1.09589 3.47813(isobutylamino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 4515-cyclopropyl-N-((2R,4S)-1-((6- 462.1 >10(isobutylamino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 4525-cyclopropyl-N-((2S,4R)-1-((6- 462.1 >10(isobutylamino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 4535-cyclopropyl-N-((2R,4R)-1-((6- 462.1 7.19308 >10(isobutylamino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 4545-cyclopropyl-N-((2R,4R)-1-((6- 476.3 >10 >10(isobutyl(methyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 455 5-cyclopropyl-N-((2R,4R)-1-((6-((2- 478.25 >10 >10 methoxyethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 4565-cyclopropyl-N-((2R,4S)-1-((6-((2- 464   >10methoxyethyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 457 5-cyclopropyl-N-((2R,4R)-1-((6-((2- 464.25 >10 >10 methoxyethyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 4585-cyclopropyl-N-((2S,4S)-2-methyl-1-((6- 519.3 0.13177 0.58095((2-morpholinoethyl)amino)pyridin-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 4595-cyclopropyl-N-((2R,4R)-2-methyl-1-((6-  519.35 2.35941 4.57896((2-morpholinoethyl)amino)pyridin-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 4605-cyclopropyl-N-((2R,4R)-2-methyl-1-((6- 533.3 >10 >10 (methyl(2-morpholinoethyl)amino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 461 N-((2S,4S)-1-((6-((2-  463.25 0.01418 3.85496aminoethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 462 N-((2S,4R)-1-((6-((2- 463.30.3055 aminoethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 463 N-((2R,4R)-1-((6-((2- 463  0.16261 4.33037 aminoethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 464 N-((2R,4R)-1-((6-((2-  449.250.08973 3.30448 aminoethyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 4655-cyclopropyl-N-(9-((6- 488.1 3.11956 6.16422(isobutylamino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 466N-((2S,4S)-1-((5-chloropyridin-2- 424.9 0.12114yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 4675-cyclopropyl-N-((2S,4S)-2-methyl-1-((2- 420.3 3.73627 5.75977(methylamino)pyridin-3- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 468 methyl 1-((1r,4r)-4-aminocyclohexane-1- 433.2 1.22465carbonyl)-4-(5-cyclopropylisoxazole-3-carboxamido)-5-methylpiperidine-3- carboxylate 469N-(1-((1r,4r)-4-aminocyclohexane-1- 437.2 6.27588carbonyl)-3-phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide470 N-(1-((3-aminopropyl)sulfonyl)-3- 433.1 2.7581phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 471 methyl1-(4-aminobutanoyl)-4-(5- 393.1 5.75922cyclopropylisoxazole-3-carboxamido)-5- methylpiperidine-3-carboxylate472 5-cyclopropyl-N-(9-((2- 502.2 >10 (isobutyl(methyl)amino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3- yl)isoxazole-3-carboxamide 4735-cyclopropyl-N-(9-((2- 488.1 5.97434(isobutylamino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 4745-cyclopropyl-N-((2S,4S)-1-((2- 462.2 2.73729(isobutylamino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 475 N-((2S,4S)-1-((2-((2-449   0.08652 1.34483 aminoethyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 476N-(9-((2-((2-aminoethyl)amino)pyridin-3- 475   1.30942yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 477 N-((2S,4S)-1-((3- 433.20.93164 3.26041 carbamoylphenyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 478N-((2S,4S)-1-(4-benzylpiperazine-1- 452.3 >10 >10carbonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide479 N-((2R,4R)-1-(4-(1- 424.1 0.28891 2.02944aminocyclobutyl)benzoyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 480N-((2R)-1-((3-aminopropyl)sulfonyl)-2- 433.1 0.06583 2.23715phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 481N-((2S)-1-((3-aminopropyl)sulfonyl)-2- 433.1 0.47891 4.47317phenylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 4825-cyclopropyl-N-((2S,4S)-2-methyl-1- 384   0.92833 2.83154((tetrahydrofuran-3-yl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide483 N-((2S,4S)-1-((1H-imidazol-4- 380   0.53253 2.12754yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 484 N-((1R,3s,5S)-8-((3-  383.150.0792 1.44334 aminopropyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 485 N-((1R,3r,5S)-8-((3- 383.20.00507 0.12898 aminopropyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 486 N-((1R,3S,5S)-8-((1s,4S)-4-387.2 >10 aminocyclohexane-1-carbonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 4875-cyclopropyl-N-((1R,3r,5S)-8- 395   (pyrrolidin-3-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 4885-cyclopropyl-N-(9-((piperidin-3- 437.1 0.04505 0.85719ylmethyl)sulfonyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 489 5-cyclopropyl-N-((1R,3s,5S)-8-((4- 522.1 5.41877 6.66386(isonicotinamido)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 490N-((1R,3s,5S)-8-((6-chloro-2-oxoindolin-  491.15 9.23127 >105-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 491N-((1R,3s,5S)-8-((5-chloro-2-oxo-2,3-  493.15 >10 >10dihydrobenzo[d]oxazol-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 492N-((1R,3r,5S)-8-((5-chloro-2-oxo-2,3-  493.15 >10dihydrobenzo[d]oxazol-6-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 4935-cyclopropyl-N-((1R,3s,5S)-8-((2- 457   0.84167 2.74654oxoindolin-5-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 494 5-cyclopropyl-N-((1R,3s,5S)-8-((2-oxo- 458   5.182222,3-dihydro-1H-benzo[d]imidazol-5-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 4955-cyclopropyl-N-((1R,3s,5S)-8-((3-  453.25 >10 >10morpholinopropyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 496 5-cyclopropyl-N-((1R,3r,5S)-8-((3-  453.25 0.161990.85436 morpholinopropyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 497N-((2S,4S)-2-benzyl-1-((3-  517.35 >10 >10morpholinopropyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 498 N-((2R,4S)-2-benzyl-1-((3- 517.35 9.95967 >10 morpholinopropyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 499 N-((2R,4S)-2-benzyl-1-((2-503.1 >10 >10 morpholinoethyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 500 N-((2S,4S)-1-((3- 461.1 0.008130.10571 (benzylamino)propyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 501N-((2R,4S)-1-((3-aminopropyl)sulfonyl)- 399.1 4.487982-isopropylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 502N-((2S,4R)-1-((3-aminopropyl)sulfonyl)- 399.1 0.76582 >102-isopropylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 503N-((2R,4R)-1-((3-aminopropyl)sulfonyl)- 399.1 1.06393 >102-isopropylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 5045-cyclopropyl-N-((2R,4S)-1-((6-((2- 478.1 >10 >10methoxyethyl)(methyl)amino)pyridin-3- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 505 5-cyclopropyl-N-((2S,4R)-1-((6-((2-464   >10 >10 methoxyethyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 5065-cyclopropyl-N-((2R,4S)-2-methyl-1-((6-  519.35 3.96727 >10((2-morpholinoethyl)amino)pyridin-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 5075-cyclopropyl-N-((2S,4R)-2-methyl-1-((6-  519.35 5.54025 >10((2-morpholinoethyl)amino)pyridin-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 508N-((2R,4S)-1-((6-((2- 463   0.31958 aminoethyl)(methyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 509 N-((2S,4S)-1-((6-((2- 449.10.00592 aminoethyl)amino)pyridin-3-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 5105-cyclopropyl-N-((2S,4S)-1-((2- 476.3 >10(isobutyl(methyl)amino)pyridin-4- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 511 5-cyclopropyl-N-((2S,4R)-1-((2- 476.3 >10(isobutyl(methyl)amino)pyridin-4- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 512 N-((2R,4S)-1-((2-((2-  463.25 0.4872aminoethyl)(methyl)amino)pyridin-4-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 513 N-((2S,4S)-1-((6-cyanopyridin-3-416.1 1.09324 yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 514 5-cyclopropyl-N-(9-((6- 502.2 >10(isobutyl(methyl)amino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3- yl)isoxazole-3-carboxamide 515N-(9-((6-((2-aminoethyl)amino)pyridin-3- 475.2 0.01762yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 516N-(9-((6-((3-aminopropyl)amino)pyridin- 489.1 0.074233-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 517 N-(9-((6-((3- 503.2 0.08028aminopropyl)(methyl)amino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5185-cyclopropyl-N-((2S,4S)-1-(N,N- 385.1 3.7176diethylsulfamoyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 5195-cyclopropyl-N-((2S,4S)-2-methyl-1-((6- 0.20407(trifluoromethyl)pyridin-2- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 520 N-((2S,4S)-1-((6-((3-  463.25 0.05007aminopropyl)amino)pyridin-2- yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5215-cyclopropyl-N-((2S,4S)-2-methyl-1-((6- 533.2 4.50489 (methyl(2-morpholinoethyl)amino)pyridin-2- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 522 N-((2S,4S)-1-((6-aminopyridin-3- 406   0.40714yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 523 N-((2S,4S)-1-((2-aminopyridin-3-406   1.0836 yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 524 5-cyclopropyl-N-(9-((2- 446.21.84758 (methylamino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 525N-((1R,3r,5S)-8-((4- 423.3 0.0008 0.009 aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 5265-cyclopropyl-N-((1R,3r,5S)-8-  437.25 0.001 0.015((piperidin-4-ylmethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5275-cyclopropyl-N-((1R,3r,5S)-8-(piperazin- 410.0 0.003 0.0321-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide*IC₅₀ values are an average of n = 1 to n = 50

TABLE 2A LCMS SMYD3 SMYD3 M + H Biochem Cell Cpd. or IC₅₀ IC₅₀ No.Chemical Name (M + Na) (μM)* (μM)* 5285-cyclopropyl-N-((1R,3r,5S)-8-(((1-(4,4,4- 533 0.0006 0.0231trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 529N-((2S,4S)-1-((4-aminopiperidin-1- 412 0.0008 0.0152yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5305-cyclopropyl-N-((2S,4S)-2-methyl-1-   515.1 0.0009 0.0239(((1-phenethylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 531 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-(2-467 0.0009 0.0331 hydroxyethyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 532N-((1R,3r,5S)-8-((4-aminopiperidin-1- 424 0.0009 0.0214yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5335-cyclopropyl-N-((2S,4S)-2-methyl-1- 425 0.0010 0.0308(((1-methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 534 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-(3-481 0.0011 0.0277 hydroxypropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5355-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 426 0.0012 0.0212(methylamino)piperidin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 536 N-((1R,3r,5S)-8-(((1-benzylpiperidin-4- 513 0.00120.0580 yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5375-cyclopropyl-N-((2R,4R)-2-methyl-1-   515.05 0.0013 0.0725(((1-phenethylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 538 5-cyclopropyl-N-((2S,4S)-1-(((1-(2- 4550.0013 0.0294 hydroxyethyl)piperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 539N-((1R,3R,5S)-8-(((1r,4R)-4-   423.05 0.0013 0.0134aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 540 N-((1R,3R,5S)-8-(((1s,4S)-4- 4230.0013 0.0152 aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 541N-((2S,4S)-1-((4-(2-aminopropan-2- 447 0.0014 0.0259yl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5425-cyclopropyl-N-((1R,3r,5S)-8-(((1-(3- 495 0.0016 0.0496methoxypropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5435-cyclopropyl-N-((1R,3r,5S)-8-   423.2 0.0018 0.0445((piperidin-4-ylmethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 544N-((2S,4S)-1-(((1-benzylpiperidin-4-   501.1 0.0019 0.0447yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5455-cyclopropyl-N-((2S,4S)-1-((4- 440 0.0020 0.0399(dimethylamino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 546N-((2S,4S)-1-((4-(benzylamino)piperidin- 502 0.0021 0.03601-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 547 5-cyclopropyl-N-((1R,3r,5S)-8-  423.3 0.0023 0.0704 ((piperidin-3-ylmethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 548N-((2S,4S)-1-((4-aminobutyl)sulfonyl)-2- 385 0.0024 0.0941methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 5495-cyclopropyl-N-((1R,3r,5S)-8-(((1-(2- 534 0.0025 0.3124(piperidin-1-yl)ethyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5505-cyclopropyl-N-((2S,4S)-1-(((1-   453.05 0.0026 0.1685isopropylpiperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 5515-cyclopropyl-N-((1R,3r,5S)-8-(((1-(3,3,3- 519 0.0029 0.0542trifluoropropyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 552N-((1R,3r,5S)-8-((6-amino-2- 436 0.0031 0.0492azaspiro[3.3]heptan-2-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5535-cyclopropyl-N-((2S,4S)-2-methyl-1-   522.15 0.0034 0.1059(((1-(2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 5545-cyclopropyl-N-((2S,4S)-1-(((1-(2-   469.1 0.0035 0.0704methoxyethyl)piperidin-4- yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 555 N-((2S,4S)-1-((3,8- 424 0.0037 0.0239diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5565-cyclopropyl-N-((1R,3r,5S)-8-(((1-(2- 481 0.0039 0.0557methoxyethyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5575-cyclopropyl-N-((2S,4S)-1-(((1-   467.1 0.0042 0.2607isobutylpiperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 5585-cyclopropyl-N-((2S,4S)-2-methyl-1-   398.2 0.0043 0.0719(piperazin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 559N-((1R,3r,5S)-8-((2,7- 450 0.0047 0.0319diazaspiro[3.5]nonan-2-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5605-cyclopropyl-N-((1R,3r,5S)-8-((8- 450 0.0048 0.0516methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 5615-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 399 0.0051(methylamino)butyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 5625-ethyl-N-((1R,3r,5S)-8-((piperidin-4- 411 0.0052 0.0615ylmethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 563 5-cyclopropyl-N-((1R,3r,5S)-8-((3-((2- 440 0.0053 0.3386(methylamino)ethyl)amino)propyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 564 N-((1R,3r,5S)-8-((3-((2- 426 0.00530.1660 aminoethyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 5655-cyclopropyl-N-((2S,4S)-2-methyl-1-((8- 438 0.0060 0.0494methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 5665-cyclopropyl-N-((2S,4S)-2-methyl-1-((3- 529 0.0061 0.3222 ((4-(trifluoromethyl)benzyl)amino)propyl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 567 N-((3S,4R)-1-((4-aminopiperidin-1- 4120.0061 0.1131 yl)sulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5685-cyclopropyl-N-((2R,4R)-2-methyl-1-   425.1 0.0063 0.1559(((1-methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 569 5-cyclopropyl-N-((1R,3R,5S)-8-((((R)- 4230.0066 0.0394 piperidin-3-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 570N-((2S,4S)-1-((2,5- 410 0.0067 0.0839diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)- 2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 571 N-((1R,3r,5S)-8-((3,6- 422 0.00750.0992 diazabicyclo[3.1.1]heptan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 5725-cyclopropyl-N-((2S,4S)-2-methyl-1- 412 0.0078 0.0536(((S)-3-methylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 573 N-((2R,4R)-1-(((1-benzylpiperidin-4-   501.1 0.00800.2933 yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5745-cyclopropyl-N-((2S,4S)-2-methyl-1-((1- 411 0.0080 0.1047methylpiperidin-4-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide575 5-cyclopropyl-N-((1R,3S,5S)-8-((((S)- 423 0.0080 0.0674piperidin-3-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5765-cyclopropyl-N-((2S,4S)-1-((4- 413 0.0081 0.1064(dimethylamino)butyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 577 N-((2S,4S)-1-((2,5- 424 0.0092 0.1342diazabicyclo[2.2.2]octan-2-yl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5785-cyclopropyl-N-((2S,4S)-2-methyl-1-((3- 511 0.0094 0.2887((naphthalen-2- ylmethyl)amino)propyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 579 5-cyclopropyl-N-((2R,4R)-2-methyl-1-  522.15 0.0095 0.5871 (((1-(2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 580N-((1R,3r,5S)-8-((2,6- 422 0.0097 0.0889diazaspiro[3.3]heptan-2-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 581 5-cyclopropyl-N-((2S,4S)-1-((4-454 0.0101 0.1429 (isopropylamino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 5825-cyclopropyl-N-((1R,3r,5S)-8-((6- 436 0.0101 0.1513methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 5835-cyclopropyl-N-((2R,4R)-1-(((1-(2-   469.1 0.0104 0.2343methoxyethyl)piperidin-4- yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 584 5-cyclopropyl-N-((2S,4S)-1-(((S)-3- 4260.0105 0.1586 ethylpiperazin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 585N-((2S,4S)-1-((1,4-diazepan-1- 412 0.0106 0.1857yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 586 N-((1R,3r,5S)-8-((3-((2- 4400.0107 0.2627 aminoethyl)(methyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 5875-cyclopropyl-N-((2S,4S)-2-methyl-1-   524.1 0.0107 0.3105(((1-(2-morpholinoethyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 588 N-((2S,4S)-1-((3,6- 410 0.0108 0.1505diazabicyclo[3.1.1]heptan-3-yl)sulfonyl)- 2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 5895-cyclopropyl-N-((2R,4R)-1-(((1-(2- 455 0.0109 0.1525hydroxyethyl)piperidin-4- yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 590 5-cyclopropyl-N-((1R,3r,5S)-8-((3-((2-454 0.0109 0.1751 (dimethylamino)ethyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 5915-cyclopropyl-N-((1R,3r,5S)-8-((3- 397 0.0111 0.1498(methylamino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 5925-cyclopropyl-N-((2S,4S)-2-methyl-1- 424 0.0116 0.1061(((1S,4S)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 5935-cyclopropyl-N-((1R,3r,5S)-8-((3- 411 0.0118 0.1472(dimethylamino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 594N-((1R,3r,5S)-8-(N-(2- 436 0.0120 0.6692azaspiro[3.3]heptan-6-yl)sulfamoyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 595 5-cyclopropyl-N-((2R,4S,5R)-2,5-412 0.0126 0.0778 dimethyl-1-(piperazin-1-ylsulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 596N-((1R,3r,5S)-8-((2-((2- 412 0.0128 0.3792aminoethyl)amino)ethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 5975-cyclopropyl-N-((1R,3r,5S)-8-((3- 437 0.0129 0.2169(pyrrolidin-1-yl)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 598N-((1R,3r,5S)-8-((2-((2- 426 0.0131 0.4308aminoethyl)(methyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 5995-cyclopropyl-N-((1R,3r,5S)-8-((2-((2- 440 0.0135 0.2131(dimethylamino)ethyl)amino)ethyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 600 5-cyclopropyl-N-((1R,3r,5S)-8-((3,3- 4380.0135 0.1184 dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 601N-((2S,4R,5S)-1-((3- 385 0.0143 0.3334 aminopropyl)sulfonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 602N-((1R,3r,5S)-8-((3,8- 436 0.0145 0.1319diazabicyclo[3.2.1]octan-8-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 6035-cyclopropyl-N-((1R,3r,5S)-8-((2-((2- 454 0.0147 0.2390(dimethylamino)ethyl)(methyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 6045-cyclopropyl-N-((1R,3r,5S)-8-((3-((2- 441 0.0162 0.1999methoxyethyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6055-cyclopropyl-N-((1R,3r,5S)-8-((2-((2- 426 0.0175 0.3023(methylamino)ethyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole- 3-carboxamide 6065-cyclopropyl-N-((1R,3r,5S)-8-(N-methyl- 452 0.0177 0.2351N-(1-methylpiperidin-4-yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6075-cyclopropyl-N-((2R,4R)-1-(((1-   453.05 0.0178 1.1728isopropylpiperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 6085-cyclopropyl-N-((3S,4R)-1-(((1-(3- 469 0.0178 0.2246hydroxypropyl)piperidin-4- yl)methyl)sulfonyl)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide 609 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((3-529 0.0188 0.4514 ((3-(trifluoromethyl)benzyl)amino)propyl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 610 5-cyclopropyl-N-((1R,3r,5S)-8-((3-((2-468 0.0194 0.3325 (dimethylamino)ethyl)(methyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 6115-cyclopropyl-N-((2R,4R)-1-(((1-   467.1 0.0200 1.0292isobutylpiperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 612 N-((2S,4S)-1-((3- 4670.0207 0.2172 ((cyclohexylmethyl)amino)propyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6135-cyclopropyl-N-((3S,4R)-3-methyl-1- 521 0.0209 0.2124(((1-(4,4,4-trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 614 N-((3S,4R)-1-((4-(benzylamino)piperidin-502 0.0212 0.3043 1-yl)sulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 615 N-((2S,4S)-1-((3,8- 424 0.02170.2333 diazabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6165-cyclopropyl-N-((2R,4R)-2-methyl-1-(4- 437 0.0219 0.5949(piperidin-3-yl)benzoyl)piperidin-4- yl)isoxazole-3-carboxamide 6175-cyclopropyl-N-((2S,4S)-1-((4- 426 0.0228 0.1832ethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 618 5-cyclopropyl-N-((3S,4R)-3-methyl-1- 411 0.0232 0.2196((piperidin-4-ylmethyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide619 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-(2- 536 0.0232 0.5921morpholinoethyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6205-cyclopropyl-N-((1R,3r,5S)-8-((2- 440 0.0233 0.3392 (methyl(2-(methylamino)ethyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole- 3-carboxamide 6215-cyclopropyl-N-((3S,4R)-3-methyl-1- 398 0.0234 0.2226(piperazin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 6225-cyclopropyl-N-((1R,3r,5S)-8-((3- 454 0.0234 0.4635 (methyl(2-(methylamino)ethyl)amino)propyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 623 5-cyclopropyl-N-((3S,4R)-1-(((1-(2- 4550.0237 0.2310 hydroxyethyl)piperidin-4-yl)methyl)sulfonyl)-3-methylpiperidin-4- yl)isoxazole-3-carboxamide 6245-cyclopropyl-N-((2S,4S)-2-methyl-1- 412 0.0246 0.2837(((S)-2-methylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 625 5-cyclopropyl-N-((3S,4R)-3-methyl-1- 425 0.0253 0.2236(((1-methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 626 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 4240.0253 0.1569 (((1R,4R)-5-methyl-2,5- diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 627N-((3S,4R)-1-((4-(2-aminopropan-2- 447 0.0265 0.2431yl)phenyl)sulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 628 N-((2S,4R,5S)-1-((3- 4750.0273 0.5767 (benzylamino)propyl)sulfonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6295-cyclopropyl-N-((2R,4S,5R)-2,5- 425 0.0282 0.4070dimethyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 630 5-cyclopropyl-N-((2S,4S)-1-((3- 4250.0294 0.3965 ((cyclopropylmethyl)amino)propyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 6315-cyclopropyl-N-((2S,4S)-2-methyl-1-((5- 438 0.0298 0.2985methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 6325-cyclopropyl-N-((2S,4R,5S)-2,5- 425 0.0304 0.2286dimethyl-1-((piperidin-4- ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 633 5-cyclopropyl-N-((2S,4S)-1-((3- 4130.0304 0.2912 (isopropylamino)propyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 6345-cyclopropyl-N-((2S,4S)-2-methyl-1- 412 0.0318 0.1755(((R)-3-methylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 635 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((3- 441 0.03250.3179 (neopentylamino)propyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 636 5-cyclopropyl-N-((1R,3r,5S)-8-((3- 4380.0332 0.3652 ethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6375-cyclopropyl-N-((2S,4R,5S)-2,5- 412 0.0334 0.2032dimethyl-1-(piperazin-1- ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 638 5-cyclopropyl-N-((2S,4S)-1-((3,3- 426 0.0337 0.2535dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 639 5-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 426 0.03480.2575 methyl-1,4-diazepan-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 640 5-cyclopropyl-N-((2S,4S)-1-((3- 427 0.0357 0.4801(isobutylamino)propyl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 641 5-cyclopropyl-N-((1R,3r,5S)-8-((4- 424 0.0363 0.1881methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 642N-((2R,4S,5R)-1-((3- 385 0.0376 0.5708 aminopropyl)sulfonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6435-cyclopropyl-N-((1R,3r,5S)-8-((3- 440 0.0378 0.2106(hydroxymethyl)piperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6445-cyclopropyl-N-((2R,4R)-2-methyl-1-(4- 437 0.0413 0.3031(piperidin-4-yl)benzoyl)piperidin-4- yl)isoxazole-3-carboxamide 645N-((2S,4S)-1-((3- 537 0.0444 0.5754 (benzhydrylamino)propyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6465-cyclopropyl-N-((3S,4R)-3-methyl-1-(N- 412 0.0452 0.7547(piperidin-4-yl)sulfamoyl)piperidin-4- yl)isoxazole-3-carboxamide 647N-((2S,4S)-2-benzyl-1-((piperidin-4- 487 0.0455 0.8087ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide648 5-cyclopropyl-N-((3S,4R)-1-(((1-(3- 483 0.0468 0.3307methoxypropyl)piperidin-4- yl)methyl)sulfonyl)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide 649 5-cyclopropyl-N-((1R,3r,5S)-8-((2- 3830.0472 0.2614 (methylamino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 650N-((2S,4S)-1-(N-(2- 0.0491 4.6303aminoethyl)sulfamoyl)-2-methylpiperidin- 4-yl)-5-cyclopropylisoxazole-3-carboxamide 651 5-cyclopropyl-N-((1R,3r,5S)-8-((2-(3- 466 0.0506 0.5325(dimethylamino)pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6525-cyclopropyl-N-((2R,4S)-2-methyl-1- 398 0.0511 0.3391(piperazin-1-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 6535-cyclopropyl-N-((3S,4R)-3-methyl-1-(N- 426 0.0550 0.3278methyl-N-(piperidin-4- yl)sulfamoyl)piperidin-4-yl)isoxazole-3-carboxamide 654 5-cyclopropyl-N-((3S,4R)-1-(((1-(2- 469 0.0560 0.3397methoxyethyl)piperidin-4- yl)methyl)sulfonyl)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide 655 N-((3S,4R)-1-(((1-benzylpiperidin-4- 5010.0564 0.4969 yl)methyl)sulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6565-cyclopropyl-N-((1R,3r,5S)-8-((3,3,4- 452 0.0598 0.4406trimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 657N-((2R,4S,5R)-1-(4-(2-aminopropan-2- 425 0.0634 0.6340yl)benzoyl)-2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6585-cyclopropyl-N-((2R,4R)-2-methyl-1-(4- 452 0.0647 1.3988(piperazin-1-ylmethyl)benzoyl)piperidin- 4-yl)isoxazole-3-carboxamide659 N-((1R,3r,5S)-8-(N-(1-benzylpiperidin-4- 528 0.0664 0.5776yl)-N-methylsulfamoyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 6605-cyclopropyl-N-((1R,3r,5S)-8-((3,4- 438 0.0667 0.4140dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6615-cyclopropyl-N-((2S,4S)-1-(((2S,5R)- 426 0.0773 0.49032,5-dimethylpiperazin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 662N-((2S,4S)-2-benzyl-1-(((1-(2- 531 0.0801 1.5480hydroxyethyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6635-cyclopropyl-N-((1R,3r,5S)-8-((2-(3- 506 0.0851 0.6705(piperidin-1-yl)pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 664N-((2R,4R)-1-(4-((R)-1- 397 0.0866 1.0654aminoethyl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6655-cyclopropyl-N-((1R,3r,5S)-8-((3-((2- 455 0.0868methoxyethyl)(methyl)amino)propyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 666 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 4120.0906 0.8014 (((R)-2-methylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 6675-cyclopropyl-N-((3S,4R)-3-methyl-1-(N- 426 0.0969 0.7306(1-methylpiperidin-4- yl)sulfamoyl)piperidin-4-yl)isoxazole-3-carboxamide 668 5-cyclopropyl-N-((3S,4R)-3-methyl-1-(N- 440 0.10090.5763 methyl-N-(1-methylpiperidin-4-yl)sulfamoyl)piperidin-4-yl)isoxazole-3- carboxamide 6695-cyclopropyl-N-((2S,4S)-1-(((R)-3,4- 426 0.1020 0.3984dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 670 5-cyclopropyl-N-((1R,3r,5S)-8-((3-((2- 496 0.1027 0.8858morpholinoethyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 671N-((2R,4R)-1-(4-(2- 413 0.1035 5.5778aminoethoxy)benzoyl)-2-methylpiperidin- 4-yl)-5-cyclopropylisoxazole-3-carboxamide 672 5-cyclopropyl-N-((1R,3r,5S)-8-((2- 397 0.1043 0.3883(dimethylamino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6735-cyclopropyl-N-((1R,3r,5S)-9- 437 0.1061 1.6774((piperidin-4-ylmethyl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 6745-cyclopropyl-N-((2S,4S)-2-methyl-1-(N- 440 0.1083 1.0760methyl-N-(1-methylpiperidin-4- yl)sulfamoyl)piperidin-4-yl)isoxazole-3-carboxamide 675 5-cyclopropyl-N-((2R,4R)-2-methyl-1-(4- 397 0.11051.3732 ((methylamino)methyl)benzoyl)piperidin-4-yl)isoxazole-3-carboxamide 676 5-cyclopropyl-N-((2R,4R)-2-methyl-1-  524.15 0.1112 >10.0000 (((1-(2-morpholinoethyl)piperidin-4-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 677N-((2S,4S)-1-(N-(2-aminoethyl)-N- 386 0.1112 5.3131methylsulfamoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6785-cyclopropyl-N-((1R,3r,5S)-9-(N-methyl- 452 0.1131 2.6583N-(piperidin-4-yl)sulfamoyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 679 N-((2R,4R)-1-(4-((S)-1- 397 0.1132 1.2977aminoethyl)benzoyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6805-cyclopropyl-N-((2S,4S)-2-methyl-1- 440 0.1187 0.5921((3,3,4-trimethylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 681 N-((2R,4S,5R)-1-((3- 474 0.1195 0.9296(benzylamino)propyl)sulfonyl)-2,5- dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 682 N-((2S,4S)-2-benzyl-1-(((1- 5010.1211 1.2477 methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6835-cyclopropyl-N-((2R,4R)-2-methyl-1-(6- 439 0.1217 1.7798(piperazin-1-yl)nicotinoyl)piperidin-4- yl)isoxazole-3-carboxamide 6845-cyclopropyl-N-((1R,3r,5S)-8-((3- 454 0.1225 0.9230(hydroxymethyl)-4-methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 6855-cyclopropyl-N-((2R,4S,5R)-2,5- 426 0.1244 0.2542dimethyl-1-((4-methylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 6865-cyclopropyl-N-((2R,4R)-1-(4- 411 0.1289 1.5414((dimethylamino)methyl)benzoyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 687 5-cyclopropyl-N-((1R,3s,5S)-9-(N- 452 0.1302 1.7075methyl-N-(piperidin-4-yl)sulfamoyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 688N-((2R,4S,5R)-1-((2- 371 0.1306 0.7834 aminoethyl)sulfonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 6895-cyclopropyl-N-((1R,3r,5S)-8-((2-(2- 437 0.1307 0.7636methylpyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6905-cyclopropyl-N-((1R,3r,5S)-8-((2-(3- 439 0.1376 0.5532hydroxypyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 691N-((2R,4S)-2-benzyl-1-((piperidin-4- 487 0.1440 1.9453ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide692 5-cyclopropyl-N-((1R,3r,5S)-8-((3,5- 438 0.1482 0.6374dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 6935-cyclopropyl-N-((3S,4R)-3-methyl-1- 522 0.1556 4.0418(((1-(2-(piperidin-1-yl)ethyl)piperidin-4-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 694N-((2S,4R,5S)-1-((2- 371 0.1570 0.9523 aminoethyl)sulfonyl)-2,5-dimethylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 695N-((2S,4S)-1-((3-amino-1- 447 0.1686 1.8333phenylpropyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide 696N-((3S,4R)-1-(N-(1-benzylpiperidin-4- 502 0.1703 1.5473yl)sulfamoyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 6975-cyclopropyl-N-((2S,4S)-2-methyl-1-((3- 447 0.1777 1.5607(phenylamino)propyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 6985-cyclopropyl-N-((3S,4R)-3-methyl-1- 507 0.1790 0.7457(((1-(3,3,3-trifluoropropyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 699 5-cyclopropyl-N-((2S,4S)-1-((3,4- 4260.1930 0.6578 dimethylpiperazin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 700N-((2S,4S)-2-benzyl-1-((piperidin-3- 487 0.1936 2.1088ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide701 5-cyclopropyl-N-((2S,4S)-1-((3,5- 426 0.2103 1.8410dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 702 5-cyclopropyl-N-((1R,3r,5S)-8-((3,4,5- 452 0.2151 1.2352trimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7035-cyclopropyl-N-((1R,3r,5S)-8-((3- 510 0.2170 0.8042 (methyl(2-morpholinoethyl)amino)propyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 704N-((2R,4S)-1-((3-amino-1- 447 0.2181phenylpropyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide 7055-cyclopropyl-N-((1R,3r,5S)-8-((2- 473 0.2250 1.5149(phenethylamino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7065-cyclopropyl-N-((2S,4S)-2-methyl-1- 391 0.2376 1.2126(pyridin-4-ylsulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 707N-((2S,4S)-2-benzyl-1-(((1-(3- 545 0.2469 2.5353hydroxypropyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 708 N-((2S,4S)-1-((6-aminopyridin-2-406 0.2521 1.6621 yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7095-cyclopropyl-N-((1R,5R)-9-(N-methyl- 466 0.2575 1.9155N-(1-methylpiperidin-4-yl)sulfamoyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 7105-cyclopropyl-N-((3S,4R)-3-methyl-1-((4- 412 0.2607 0.8310methylpiperazin-1-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide711 5-cyclopropyl-N-((2S,4S)-1-(((R)-3-ethyl- 440 0.2725 1.15214-methylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 712 5-cyclopropyl-N-((2S,4S)-2-methyl-1- 440 0.2749 1.0984(((2S,5R)-2,4,5-trimethylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 7135-cyclopropyl-N-((1R,3r,5S)-8-((3-ethyl- 452 0.2934 1.17574-methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 714N-((2S,4R)-2-benzyl-1-(N-methyl-N- 502 0.2949 3.1527(piperidin-4-yl)sulfamoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 715N-((2R,4S)-2-benzyl-1-(N-methyl-N- 502 0.2971 3.0425(piperidin-4-yl)sulfamoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 716 N-((2R,4R)-1-((3-amino-4- 4610.3027 3.5340 phenylbutyl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide 717N-((2S,4S)-2-benzyl-1-(pyrrolidin-3- 459 0.3061 2.0240ylsulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 7185-cyclopropyl-N-((1R,3s,5S)-9-(N- 466 0.3090 1.6220methyl-N-(1-methylpiperidin-4- yl)sulfamoyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 719 N-((3S,4R)-1-(N-(1-benzylpiperidin-4-yl)-516 0.3199 1.2054 N-methylsulfamoyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 720N-((2S,4S)-2-benzyl-1-(((1-(2- 545 0.3218 2.4270methoxyethyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 721 5-cyclopropyl-N-((1R,3s,5S)-8-423 0.3224 1.8253 ((piperidin-3-ylmethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7225-cyclopropyl-N-((1R,3r,5S)-8-((3- 486 0.3257 1.5226phenylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 723N-((2S,4R)-2-benzyl-1-((piperidin-4- 487 0.3260 2.7313ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide724 5-cyclopropyl-N-((1R,3s,5S)-8-(N- 438 0.3330 2.4407methyl-N-(piperidin-4-yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 725N-((2S,4S)-2-benzyl-1-(piperidin-3- 473 0.3401 3.0662ylsulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 726N-((1R,3r,5S)-8-((2-(3- 529 0.3596 2.4667 (benzyloxy)pyrrolidin-1-yl)ethyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 727 (E)-5-cyclopropyl-N-(1-((3- 3690.3633 1.3883 (methylamino)prop-1-en-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 7285-cyclopropyl-N-((2S,4S)-1-(((R)-3- 454 0.3805 1.3655isopropyl-4-methylpiperazin-1- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 729 5-cyclopropyl-N-((1R,3s,5S)-8-(piperidin-409 0.4110 2.5264 3-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 730 N-((1R,3r,5S)-9-((2-aminopyridin-4- 4320.4128 1.3188 yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 7315-cyclopropyl-N-((2S,4R,5S)-2,5- 426 0.4183 1.3321dimethyl-1-((4-methylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 7325-cyclopropyl-N-((2S,4R,5S)-2,5- 425 0.4313 1.4616dimethyl-1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 733N-((1R,5R)-9-((5-chloropyridin-2- 451 0.4417 1.9585yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 734 N-((1R,3r,5S)-9-((2-((3-489 0.4425 4.1727 aminopropyl)amino)pyridin-3-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 7355-cyclopropyl-N-((2S,4S)-1-(((S)-3,4- 426 0.4458 1.3552dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 736 N-((2S,4S)-1-((3-benzylpiperazin-1- 488 0.4521 2.0254yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 737N-((2S,4S)-1-((2-benzylpiperazin-1- 488 0.4692 6.9424yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7385-cyclopropyl-N-((3S,4R)-3-methyl-1- 524 0.4765 2.8209(((1-(2-morpholinoethyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 739 5-cyclopropyl-N-((1R,3r,5S)-8-((2- 4310.4911 2.3968 (pyridin-4-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 740N-((1R,3s,5S)-9-((6-aminopyridin-2- 432 0.4976yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 7415-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 405 0.5123methylpyridin-2-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 7425-cyclopropyl-N-((1R,3r,5S)-8-((2- 496 0.5129 0.8991 (methyl(2-morpholinoethyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7435-cyclopropyl-N-((1R,3r,5S)-8-((2-((2- 482 0.5137 1.8184morpholinoethyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 744N-((2R,4R)-2-benzyl-1-((piperidin-4- 487 0.5179 2.3476ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide745 N-((2S,4S)-2-benzyl-1-((pyrrolidin-2- 473 0.5333 2.6361ylmethyl)sulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide746 5-cyclopropyl-N-((2R,4S,5R)-2,5- 425 0.5406 1.6619dimethyl-1-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole- 3-carboxamide 7475-cyclopropyl-N-((2R,4R)-2-methyl-1-(1- 408 0.5828 2.4138methyl-1H-benzo[d]imidazole-5- carbonyl)piperidin-4-yl)isoxazole-3-carboxamide 748 5-cyclopropyl-N-((1R,3r,5S)-8-((2- 487 0.5844 3.1758(methyl(phenethyl)amino)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 749N-((1R,3r,5S)-8-((3-benzylpiperazin-1- 500 0.5903 3.5562yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 750N-((2S,4S)-2-benzyl-1-(((1-(3- 559 0.6247 3.4693methoxypropyl)piperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7515-cyclopropyl-N-((2S,4S)-2-methyl-1- 474 0.6332 2.8860(((R)-3-phenylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 752 N-((2R,4R)-2-benzyl-1-(pyrrolidin-3- 459 0.6667 2.4929ylsulfonyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 7535-cyclopropyl-N-((1R,3s,5S)-9-((5- 435 0.6723 2.0403fluoropyridin-3-yl)sulfonyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 754 N-((2S,4S)-1-(N-(2-chloro-6- 471 0.6757 3.7071fluorobenzyl)sulfamoyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7555-cyclopropyl-N-((2S,4S)-2-methyl-1- 440 0.6773 2.3828(((3S,5R)-3,4,5-trimethylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 756N-((2S,4S)-1-((2-aminopyridin-4- 406 0.6839 1.7689yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 757N-((2R,4R)-2-benzyl-1-(N-methyl-N- 502 0.7255 7.6085(piperidin-4-yl)sulfamoyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 758 N-((1R,3r,5S)-8-((3-oxa-7,9-452 0.7306 1.6477 diazabicyclo[3.3.1]nonan-7-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 7595-cyclopropyl-N-((2S,4S)-1-(((R)-3-(2- 456 0.7327 2.0633hydroxyethyl)-4-methylpiperazin-1- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 760 5-cyclopropyl-N-(1-(4-methylpiperidine-361 0.7416 4-carbonyl)piperidin-4-yl)isoxazole-3- carboxamide 761N-((2S,4S)-1-((4- 461 0.7514 2.8538 (acetamidomethyl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 7625-cyclopropyl-N-((1R,3r,5S)-8-((2-(2- 467 0.7698 2.0670(methoxymethyl)pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7635-cyclopropyl-N-((1R,3S)-9-((5- 431 0.7704methylpyridin-2-yl)sulfonyl)-9- azabicyclo[3.3.1]nonan-3-yl)isoxazole-3-carboxamide 764 5-cyclopropyl-N-((2R,4R)-2-methyl-1-(4- 482 0.80619.6655 (2-(piperazin-1- yl)ethoxy)benzoyl)piperidin-4-yl)isoxazole-3-carboxamide 765 5-cyclopropyl-N-((1R,5R)-9-((4- 4520.8362 2.4208 ethylpiperazin-1-yl)sulfonyl)-9-azabicyclo[3.3.1]nonan-3-yl)isoxazole-3- carboxamide 766N-((1R,3r,5S)-8-((4-(2-aminopropan-2- (481) yl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide *IC₅₀values are an average of n = 1 to n = 50

TABLE 3A LCMS SMYD3 SMYD3 M + H Biochem Cell Cpd. or IC₅₀* IC₅₀* No.Chemical Name (M + Na) (uM) (uM) 7675-cyclopropyl-N-((1R,3R,5S)-8-(((1S,4S)- 467.00 0.0004 0.01945 4-((2-hydroxyethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7685-cyclopropyl-N-((1R,3R,5S)-8-(((1R,4R)- 467.00 0.00071 0.03468 4-((2-hydroxyethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7695-cyclopropyl-N-((1R,3r,5S)-8-((7- 554.00 0.00076 0.01791phenethyl-2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 7705-cyclopropyl-N-((1R,3r,5S)-8-(((1- 437.00 0.00088 0.01916methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7715-cyclopropyl-N-((1R,3R,5S)-8-(((1s,4S)- 451.00 0.00094 0.025554-(dimethylamino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 772N-((2S,4S)-1-((((1S,3S)-3- 411.00 0.00095 0.03265aminocyclopentyl)methyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 773 N-((2S,4S)-1-(((1r,4S)-4- 411.000.00103 0.01771 aminocyclohexyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 774N-((2S,4S)-1-((4-amino-4-methylpiperidin- 426.00 0.00104 0.02561l-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7755-cyclopropyl-N-((2R,4R)-2-ethyl-1-(((1- 439.00 0.00107 0.01437methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 776 N-((1R,3R,5S)-8-(((1r,4R)-4- 513.000.00112 0.02758 (benzylamino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 7775-cyclopropyl-N-((2R,4R)-1-(((1- 453.00 0.00114 0.01698methylpiperidin-4-yl)methyl)sulfonyl)-2-propylpiperidin-4-yl)isoxazole-3- carboxamide 7785-cyclopropyl-N-((1R,3r,5S)-8-(((1-(4- 531.00 0.00118 0.04475fluorobenzyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7795-ethyl-N-((1R,3r,5S)-8-(((1-(4,4,4- 521.00 0.0012 0.02811trifluorobutyl)piperidin-4- yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7805-cyclopropyl-N-((2S,4S)-1-((4-((2- 470.00 0.00121 0.02389hydroxyethyl)(methyl)amino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 7815-cyclopropyl-N-((1R,3r,5S)-8-(((1- 465.00 0.00122 0.02703propylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7825-cyclopropyl-N-((1R,3r,5S)-8-((7-methyl- 464.00 0.00123 0.030092,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 783N-((2S,4S)-1-((3- 411.00 0.00124 0.05168(aminomethyl)cyclopentyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 784 N-((2S,4S)-1-((((1R,3R)-3- 411.000.00129 0.03928 aminocyclopentyl)methyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 7855-cyclopropyl-N-((1R,3r,5S)-8-(((1- 451.00 0.00136 0.04408ethylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7865-cyclopropyl-N-((1R,3R,5S)-8-(((1r,4R)- 437.00 0.00137 0.03584-(methylamino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7875-cyclopropyl-N-((1R,3r,5S)-8-(((1- 465.00 0.00138 0.03859isopropylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7885-ethyl-N-((1R,3R,5S)-8-(((1r,4R)-4-((2- 455.00 0.00142 0.03076hydroxyethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 789N-((1R,3R,5S)-8-(((1r,4R)-4- 411.00 0.00159 0.03186aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-ethylisoxazole-3-carboxamide 790 N-((3S,4R)-1-(((1r,4S)-4- 433.000.00181 0.056 aminocyclohexyl)sulfonyl)-3- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 7915-cyclopropyl-N-((1R,3r,5S)-8-((4- 528.00 0.00182 0.0404(phenethylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7925-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 468.00 0.00185 0.04492hydroxyethyl)amino)piperidin-1- yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 793 N-((2S,4S)-1-((4-aminopiperidin-1- 400.200.00185 0.02625 yl)sulfonyl)-2-methylpiperidin-4-yl)-5-ethylisoxazole-3-carboxamide 7945-cyclopropyl-N-((1R,3r,5S)-8-((4-((4,4,4- 534.00 0.00187 0.03473trifluorobutyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 7955-cyclopropyl-N-((2S,4S)-2-methyl-1-((2- 425.00 0.00187 0.02758((S)-1-methylpyrrolidin-3- yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 796 N-((1R,3r,5S)-8-((4-amino-4- 438.00 0.0019 0.04067methylpiperidin-1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 797 5-ethyl-N-((1R,3r,5S)-8-(((1-425.00 0.0019 0.04267 methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 7985-cyclopropyl-N-((1R,3R,5S)-8-(((1s,4S)- 437.00 0.00191 0.030454-(methylamino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 799N-((1R,3r,5S)-8-((4-aminopiperidin-1- 412.00 0.00205 0.03459yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-ethylisoxazole-3-carboxamide 800N-((2S,4S)-1-((4-amino-3-methylpiperidin- 426.00 0.00218 0.03972l-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 801 N-((1R,3r,5S)-8-((6-amino-3-422.00 0.00219 0.02773 azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8025-cyclopropyl-N-((2S,4S)-2-methyl-1-(((3- 425.00 0.0023 0.02696(methylamino)cyclopentyl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 803 N-((1R,3r,5S)-8-((4-amino-2-438.00 0.00231 0.05897 methylpiperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 804N-((2S,4S)-1-((1,8-diazaspiro[4.5]decan-8- 452.00 0.00236 0.06082yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 8055-cyclopropyl-N-((1R,3r,5S)-8-((4- 452.00 0.00239 0.05324(dimethylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 806N-((2S,4S)-1-((3-aminopropyl)sulfonyl)-2- 399.00 0.0024 0.11318propylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 8075-cyclopropyl-N-((1R,3R,5S)-8-(((1r,4R)- 451.00 0.00244 0.085694-(dimethylamino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8085-cyclopropyl-N-((2S,4S)-1-((4-((2- 456.00 0.00247 0.03681hydroxyethyl)amino)piperidin-1- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 809 5-cyclopropyl-N-((1R,3r,5S)-8-(((1-479.00 0.00249 0.04268 isobutylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 810N-((1R,3r,5S)-8-((4- 514.00 0.00253 0.07225(benzylamino)piperidin-1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 811N-((2S,4S)-1-((4-(2-aminopropan-2- 435.00 0.00258 0.03361yl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5-ethylisoxazole-3-carboxamide 8125-cyclopropyl-N-((1R,3r,5S)-8-((4- 438.00 0.00265 0.04108(methylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 813N-((2S,4S)-1-((1,7-diazaspiro[3.5]nonan-7- 438.00 0.00273 0.03566yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 8145-cyclopropyl-N-((2S,4S)-2-methyl-1-((2- 425.00 0.00277 0.04417((R)-1-methylpyrrolidin-3- yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 815 N-((1R,3R,5S)-8-(((1s,4S)-4- 411.00 0.00278 0.05262aminocyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-ethylisoxazole-3-carboxamide 8165-cyclopropyl-N-((1R,3S,5S)-8-(((S)-1-(1- 451.00 0.00291 0.05232methylpiperidin-4-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 817N-((1R,3r,5S)-8-((3,8- 436.00 0.00311 0.0348diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8185-cyclopropyl-N-((1R,3r,5S)-8-((7- 506.00 0.00313 0.05544isobutyl-2,7-diazaspiro[3.5]nonan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 819N-((2S,4S)-1-((((1R,3R)-3- 425.00 0.0032 0.12419aminocyclohexyl)methyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 8205-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 482.00 0.00327 0.05743hydroxyethyl)(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8215-cyclopropyl-N-((1R,3r,5S)-8-((4- 494.00 0.00328 0.05852(isopentylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8225-cyclopropyl-N-((1R,3r,5S)-8-((8-ethyl- 464.00 0.00344 0.043743,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8235-cyclopropyl-N-((2S,4S)-1-(((3- 439.00 0.0035 0.06716(dimethylamino)cyclopentyl)methyl)sulfonyl)-2-memylpiperidin-4-yl)isoxazole-3- carboxamide 824N-((1R,3r,5S)-8-((7-benzyl-2,7- 540.00 0.00387 0.08042diazaspiro[3.5]nonan-2-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 8255-cyclopropyl-N-((1R,3R,5S)-8-(((1r,4R)- 481.00 0.00391 0.05526 4-((2-methoxyemyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8265-cyclopropyl-N-((1R,3R,5S)-8-(((1s,4S)- 481.00 0.00392 0.0584 4-((2-methoxyethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 827N-((2S,4S)-1-(((3- 425.00 0.004 0.07273aminocyclohexyl)methyl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 828 N-((2S,4S)-1-((3,6- 410.000.00418 0.14958 diazabicyclo[3.1.1]heptan-6-yl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 8295-cyclopropyl-N-((2S,4S)-1-((4- 440.00 0.0043 0.07016(ethylamino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 830 N-((1R,3r,5S)-8-((4-438.00 0.00434 1.55122 (aminomethyl)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 831N-((1R,3r,5S)-8-((4-amino-3- 438.00 0.00436 0.08513methylpiperidin-1-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 832 N-((1R,3r,5S)-8-((3,6- 422.000.00438 0.13361 diazabicyclo[3.1.1]heptan-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8335-ethyl-N-((1R,3R,5S)-8-(((1s,4S)-4-((2- 455.00 0.00447 0.07223hydroxyethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8345-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 496.00 0.00457 0.04872hydroxypropyl)(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 835N-((1R,3r,5S)-8-((1,8-diazaspiro[4.5]decan- 464.00 0.00463 0.117818-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 836 N-((2S,4S)-1-((((1S,3S)-3-425.00 0.00464 0.08897 aminocyclohexyl)methyl)sulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 8375-cyclopropyl-N-((3S,4R)-1-(((1r,4S)-4- 439.00 0.00482 0.08441(dimethylamino)cyclohexyl)sulfonyl)-3- methylpiperidin-4-yl)isoxazole-3-carboxamide 838 5-cyclopropyl-N-((1R,3r,5S)-8-((4- 548.00 0.0049 0.05236(methyl(4,4,4- trifluorobutyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 839N-((2S,4S)-1-((4- 516.00 0.00497 0.15413(benzyl(methyl)amino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 840 N-((1R,3r,5S)-8-((2,5- 422.000.00501 0.05595 diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8415-cyclopropyl-N-((2S,4S)-2-methyl-1-((2- 411.00 0.00505 0.12354((S)-pyrrolidin-3- yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 842 5-cyclopropyl-N-((1R,3R,5S)-8-(((R)-1- 437.00 0.00510.02901 (piperidin-4-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8435-cyclopropyl-N-((2S,4S)-1-((4- 468.00 0.00511 0.07768(isobutylamino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 8445-cyclopropyl-N-((1R,3r,5S)-8-((4- 542.00 0.00528 0.30533(methyl(phenethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8455-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 482.00 0.0053 0.08635hydroxypropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8465-cyclopropyl-N-((1R,3r,5S)-8-((4- 508.00 0.00536 0.08024(isopentyl(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8475-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 466.00 0.00553 0.07581(pyrrolidin-1-yl)piperidin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 848 5-cyclopropyl-N-((1R,3r,5S)-8-((4-((4- 532.00 0.005730.15298 fluorobenzyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 849N-((1R,3r,5S)-8-((1,7- 450.00 0.00595 0.06199diazaspiro[3.5]nonan-7-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 8505-cyclopropyl-N-((1R,3r,5S)-8-((8-(3- 494.00 0.00621 0.05877hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8515-cyclopropyl-N-((2S,4S)-1-((4-((2- 484.00 0.00644 0.12457methoxyethyl)(methyl)amino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide 8525-cyclopropyl-N-((1R,3r,5S)-8-((4- 466.00 0.0065 0.1142(ethyl(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8535-cyclopropyl-N-((1R,3r,5S)-8-((4- 480.00 0.00655 0.07104(isobutylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8545-cyclopropyl-N-((2S,4S)-2-methyl-1- 411.00 0.00692 ((((S)-piperidin-3-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 855N-((1R,3r,5S)-8-((2,5- 436.00 0.00706 0.06866diazabicyclo[2.2.2]octan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8565-cyclopropyl-N-((1R,3r,5S)-8-(piperazin- 410.00 0.00709 0.046681-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8575-cyclopropyl-N-((1R,3r,5S)-8-(((2,6- 451.00 0.00709 0.12971dimethylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8585-cyclopropyl-N-((2S,4S)-2-methyl-1-((2- 411.00 0.0072 0.1723((R)-pyrrolidin-3- yl)ethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 859 5-cyclopropyl-N-((1R,3R,5S)-8-(((1r,4R)- 536.000.00743 0.20891 4-((2- morpholinoethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole- 3-carboxamide 8605-cyclopropyl-N-((1R,3r,5S)-8-((4- 494.00 0.00752 0.13926(isobutyl(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8615-cyclopropyl-N-((2S,4S)-1-((4-((2- 470.00 0.00765 0.10238methoxyethyl)amino)piperidin-1- yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3-carboxamide 862 5-cyclopropyl-N-((1R,3r,5S)-8-((4- 480.000.00769 0.07647 (methyl(propyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8635-cyclopropyl-N-((1R,3r,5S)-8-((4- 466.00 0.00777 0.07998(propylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8645-cyclopropyl-N-((1R,3r,5S)-8-((5-methyl- 436.00 0.00822 0.086222,5-diazabicyclo[2.2.1]heptan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8655-cyclopropyl-N-((1R,3r,5S)-8-((4- 452.00 0.00855 0.09024(ethylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8665-cyclopropyl-N-((1R,3r,5S)-8-((8- 492.00 0.00863 0.20103isobutyl-3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8675-cyclopropyl-N-((1R,3r,5S)-8-((8- 540.00 0.00867 0.84417phenethyl-3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8685-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 535.00 0.00868 0.31004(pyrrolidin-1-yl)propyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8695-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 496.00 0.00905 0.11703methoxypropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8705-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 482.00 0.00934 0.13021methoxyethyl)amino)piperidin-1- yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 871 N-((1R,3R,5S)-8-(((1r,4R)-4- 425.000.00938 0.08674 aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- isopropylisoxazole-3-carboxamide 8725-cyclopropyl-N-((2S,4S)-1-((4- 468.00 0.00946 0.18336(diethylamino)piperidin-1-yl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 873N-((3S,4R)-1-(((1s,4R)-4- 411.00 0.00962 0.16925aminocyclohexyl)sulfonyl)-3- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 8745-cyclopropyl-N-((1R,3r,5S)-8-((4- 549.00 0.00987 0.23671(methyl(3-(pyrrolidin-1- yl)propyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8755-cyclopropyl-N-((2S,4S)-2-methyl-1- 411.00 0.01 ((((R)-piperidin-3-yl)methyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 8765-cyclopropyl-N-((1R,3R,5S)-8-(((R)-1-(1- 451.00 0.01 0.18571methylpiperidin-4-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8775-cyclopropyl-N-((1R,3S,5S)-8-(N- 438.00 0.01002 0.17551((2R,4S)-2-methylpiperidin-4- yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 878 N-((1R,3R,5S)-8-(((R)-azepan-3- 423.000.01009 0.24072 yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 8795-isopropyl-N-((1R,3r,5S)-8-(((1- 439.00 0.01066 0.2063methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 880N-((1R,3r,5S)-8-((4- 528.00 0.01085 0.45474(benzyl(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 8815-cyclopropyl-N-((1R,3r,5S)-8-((8-(2- 480.00 0.01091 0.06886hydroxyethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8825-cyclopropyl-N-((1R,3S,5S)-8-(((S)-1- 437.00 0.01118 0.08563(piperidin-4-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 883N-((1R,3S,5S)-8-(((S)-azepan-3- 423.00 0.01204 0.12799yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 884 N-((1R,3S,5S)-8-(N-((2S)-2-514.00 0.01205 0.2833 benzylpiperidin-4-yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 8855-cyclopropyl-N-((3S,4R)-3-methyl-1- 425.00 0.01209 0.15705 (((1r,4S)-4-(methylamino)cyclohexyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide886 5-cyclopropyl-N-((1R,3S,5S)-8-(N- 438.00 0.01214 0.20549((2S,4S)-2-methylpiperidin-4- yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 887 5-cyclopropyl-N-((1R,3r,5S)-8-((3- 424.000.01223 0.08778 methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8885-cyclopropyl-N-((1R,3r,5S)-8-((8-(3- 508.00 0.01243 0.11756methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8895-cyclopropyl-N-((1R,3r,5S)-8-((4- 480.00 0.01269 0.2163(diethylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 890N-((2S,4S)-1-((4-amino-2-methylpiperidin- 426.00 0.01316 0.239011-yl)sulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 891N-((1R,3R,5S)-8-(((1R,5S)-8-amino-3- 472.00 0.01331 0.14515azabicyclo[3.2.1]octan-3-yl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 8925-cyclopropyl-N-((1R,3r,5S)-8-((4-((4- 582.00 0.01346 0.26828(trifluoromethyl)benzyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 8935-cyclopropyl-N-((1R,3r,5S)-8-(N-(1- 438.00 0.01374 0.2392methylpiperidin-4-yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8945-cyclopropyl-N-((1R,3R,5S)-8-(((R)-1-(1- 527.00 0.01388 0.27989methylpiperidin-4-yl)-2- phenylethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8955-cyclopropyl-N-((1R,3r,5S)-8-((5-methyl- 450.00 0.01393 0.185942,5-diazabicyclo[2.2.2]octan-2-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 896N-((1R,3R,5S)-8-(((1r,4R)-4-amino-4- 437.00 0.01401 0.08658methylcyclohexyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 897 5-cyclopropyl-N-((1R,3r,5S)-8-(N-424.00 0.01414 0.4229 (piperidin-4-yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 8985-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 516.00 0.01431 0.24039(((R)-1-phenylethyl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 8995-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 510.00 0.01448 0.16833methoxypropyl)(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9005-cyclopropyl-N-((3S,4R)-3-methyl-1- 425.00 0.01456 0.17732 (((1s,4R)-4-(methylamino)cyclohexyl)sulfonyl)piperidin- 4-yl)isoxazole-3-carboxamide901 5-cyclopropyl-N-((1R,3r,5S)-8-((2- 424.00 0.01513 0.09768methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9025-cyclopropyl-N-((1R,3r,5S)-8-((2- 438.00 0.01524 0.15537ethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9035-cyclopropyl-N-((2S,4S)-1-(((2,6- 439.00 0.0162 0.27691dimethylpiperidin-4-yl)methyl)sulfonyl)-2-methylpiperidin-4-yl)isoxazole-3- carboxamide 904N-((1R,3r,5S)-8-((8-benzyl-3,8- 526.00 0.01688 0.39499diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 9055-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 516.00 0.01713 0.33103(((S)-1-phenylethyl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 9065-cyclopropyl-N-((1R,3r,5S)-8-((4- 478.00 0.01715 0.22884(pyrrolidin-1-yl)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9075-cyclopropyl-N-((1R,3r,5S)-8-((2,5- 438.00 0.01774 0.23784dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9085-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 525.00 0.01843 0.25328((2-morpholinoethyl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 9105-cyclopropyl-N-((2S,4S)-2-methyl-1- 397.00 0.01899 0.18648(((R)-piperidin-3-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide911 N-((1R,3r,5S)-8-((4-aminopiperidin-1- 426.00 0.02046 0.14394yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-isopropylisoxazole-3-carboxamide 9125-cyclopropyl-N-((1R,3r,5S)-8-((4-((3- 551.00 0.02093 0.31628morpholinopropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9135-cyclopropyl-N-((2S,4S)-2-methyl-1-(((S)- 397.00 0.02164 0.25547piperidin-3-yl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide 9145-cyclopropyl-N-((1R,3r,5S)-8-((8-(4,4,4- 546.00 0.02288 0.29876trifluorobutyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9155-cyclopropyl-N-((1R,3S,5S)-8-(((2S,5S)- 438.00 0.02318 0.230542,5-dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9165-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 496.00 0.02331 0.24735methoxyethyl)(methyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9175-cyclopropyl-N-((1R,3r,5S)-8-((4- 535.00 0.02491 0.37899(methyl(2-(pyrrolidin-1- yl)ethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9185-cyclopropyl-N-((1R,3r,5S)-8-((4-((3,3,3- 520.00 0.02504 0.14824trifluoropropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9195-cyclopropyl-N-((1R,3S,5S)-8-((((S)- 423.00 0.02538 0.24251piperidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9205-cyclopropyl-N-((1R,3R,5S)-8-(((1s,4S)- 536.00 0.02655 0.49882 4-((2-morpholinoethyl)amino)cyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole- 3-carboxamide 9215-cyclopropyl-N-((1R,3r,5S)-8-((2-(3-((2- 496.00 0.02768 0.37264hydroxyethyl)(methyl)amino)pyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 922 5-cyclopropyl-N-((1R,3r,5S)-8-((4-((2-521.00 0.02812 0.28224 (pyrrolidin-1-yl)ethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9235-cyclopropyl-N-((1R,3R,5S)-8-((4-(((R)-1- 528.00 0.02856 0.3101phenylethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9245-cyclopropyl-N-((1R,3r,5S)-8-((4-((2,6- 550.00 0.02889 0.66992difluorobenzyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9255-cyclopropyl-N-((1R,3r,5S)-8-((3- 452.00 0.0299 0.33958isopropylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9265-cyclopropyl-N-((1R,3R,5S)-8-(((R)-1- 423.00 0.02997 0.20921methylpiperidin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9275-cyclopropyl-N-((1R,3S,5S)-8-((4-(((S)-1- 528.00 0.03088 0.40277phenylethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9285-cyclopropyl-N-((1R,3r,5S)-8-((4- 466.00 0.03621 0.51222(isopropylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 929N-((1R,3r,5S)-8-((4- 431.00 0.03679 10 (aminomethyl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 9305-cyclopropyl-N-((1R,3S,5S)-8-((((S)- 409.00 0.03706 0.35105pyrrolidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 931N-((1R,3S,5S)-8-((4-((S)-1- 445.00 0.03725 0.52574aminoethyl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 932N-((2S,4S)-1-(((1R,5S,8R)-8-amino-3- 438.00 0.03872 0.35112azabicyclo[3.2.1]octan-3-yl)sulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 9335-cyclopropyl-N-((1R,3r,5S)-8-((3-methyl- 436.00 0.04243 0.091953,6-diazabicyclo[3.1.1]heptan-6-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 934N-((1R,3R,5S)-8-((4-((R)-1- 445.00 0.04244 0.49372aminoethyl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9355-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 539.00 0.04297 0.41384(methyl(2- morpholinoethyl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 9365-cyclopropyl-N-((1R,3r,5S)-8-((4- 565.00 0.0438 0.62258 (methyl(3-morpholinopropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9375-cyclopropyl-N-((2S,4S)-1-(((R)-2- 426.00 0.04387 0.48447ethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 938 N-((1R,3r,5S)-8-((4-((4- 539.00 0.04409 0.50761cyanobenzyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9395-cyclopropyl-N-((1R,3r,5S)-8-((2- 486.00 0.04469 0.36133phenylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 940N-((1R,3r,5S)-8-((2-benzylpiperazin-1- 522.00 0.04752yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9415-cyclopropyl-N-((1R,3r,5S)-8-((2,4,5- 452.00 0.04791 0.34078trimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 942N-((1R,3R,5S)-8-(N-((2R)-2- 514.00 0.04811 0.65877benzylpiperidin-4-yl)sulfamoyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9435-cyclopropyl-N-((1R,3S,5S)-8-((4-(((S)-1- 546.00 0.04812 0.60158(4-fluorophenyl)ethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9445-cyclopropyl-N-((1R,3R,5S)-8-((4-(((R)-1- 546.00 0.04886 0.68313(4-fluorophenyl)ethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 945N-((1R,3r,5S)-8-(N-benzyl-N-(piperidin-4- 514.00 0.05056 0.22262yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9465-cyclopropyl-N-((1R,3r,5S)-8-((4-(((2- 475.00 0.05097 0.33161hydroxyethyl)amino)methyl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole- 3-carboxamide 9475-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 537.00 0.05228 0.33809morpholinoethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 948N-((1R,3r,5S)-8-(N-(1-benzylpiperidin-4- 514.00 0.05241 0.41071yl)sulfamoyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 949N-((2S,4S)-2-benzyl-1-(N-(piperidin-4- 488.00 0.05269 1.50943yl)sulfamoyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide 9505-cyclopropyl-N-((1R,3r,5S)-8-((2,4- 438.00 0.05287 0.38988dimethylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9515-cyclopropyl-N-((1R,3r,5S)-8-(N-methyl- 438.00 0.05415 0.39515N-(piperidin-3-yl)sulfamoyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 952 5-cyclopropyl-N-((1R,3S,5S)-8-(((S)-1- 423.00 0.056210.28051 methylpiperidin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9535-cyclopropyl-N-((1R,3r,5S)-8-((4- 485.00 0.057 0.58531(pyrrolidin-1-ylmethyl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9545-cyclopropyl-N-((2S,4S)-2-ethyl-1-(((1- 439.00 0.05793 0.58254methylpiperidin-4- yl)methyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 955 5-cyclopropyl-N-((1R,3r,5S)-8-((8-(2-494.00 0.05921 0.37299 methoxyethyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9565-cyclopropyl-N-((1R,3R,5S)-8-((((R)- 409.00 0.05959 0.73276pyrrolidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9575-cyclopropyl-N-((3S,4R)-1-(((1s,4R)-4- 439.00 0.06899 0.51249(dimethylamino)cyclohexyl)sulfonyl)-3- methylpiperidin-4-yl)isoxazole-3-carboxamide 958 5-cyclopropyl-N-((1R,3r,5S)-8-((4- 502.00 0.07666 0.4864(pyrimidin-2-ylamino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 959N-((1R,3r,5S)-8-((4-(2- 445.00 0.07973 10 aminoethyl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide 9605-cyclopropyl-N-((2S,4S)-2-methyl-1- 474.00 0.08058 1.35436(((R)-2-phenylpiperazin-1- yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 961 5-cyclopropyl-N-((1R,3r,5S)-8-((4- 534.00 0.081590.36388 (methyl(3,3,3- trifluoropropyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9625-cyclopropyl-N-((1R,3r,5S)-8-((4-(2- 473.00 0.08176 0.69533(methylamino)propan-2- yl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9635-cyclopropyl-N-((1R,3r,5S)-8-((2-ethyl-4- 452.00 0.08289 0.68983methylpiperazin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9645-cyclopropyl-N-((1R,3R,5S)-8-((((R)-1- 437.00 0.08296 0.44954methylpiperidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 965N-((1R,3r,5S)-8-(((1-methylpiperidin-4- 439.00 0.08526 1.31267yl)methyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-propylisoxazole-3-carboxamide 966 N-((2S,4S)-2-benzyl-1-(piperazin-1-474.00 0.08679 1.1965 ylsulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide 9675-cyclopropyl-N-((1R,3r,5S)-8-((8-(2- 549.00 0.08702 0.50309morpholinoethyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 968N-((1R,3r,5S)-8-((4-(aminomethyl)-2- 465.00 0.08835 10chlorophenyl)sulfony1)-8- azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide 9695-cyclopropyl-N-((1R,3R,5S)-8-((((R)-1- 423.00 0.08856 0.44032methylpyrrolidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 970N-((1R,3r,5S)-8-((4-(2-aminopropan-2- 469.00 0.08926 0.74846yl)phenyl)sulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)-5-ethylisoxazole-3-carboxamide 971 5-cyclopropyl-N-((1R,3R,5S)-8-((((R)-423.00 0.09085 0.46628 piperidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9725-cyclopropyl-N-((2S,4S)-2-methyl-1-((4- 530.00 0.09327 1.27042((2-phenylpropan-2-yl)amino)piperidin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3- carboxamide 9735-cyclopropyl-N-((1R,3r,5S)-8-((4- 551.00 0.09526 1.01775 (methyl(2-morpholinoethyl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9745-cyclopropyl-N-((2S,4S)-1-(((R)-3- 426.00 0.09899 0.80662ethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 975 5-cyclopropyl-N-((2S,4S)-1-((2- 440.00 0.10112 0.91436isopropylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 976 5-cyclopropyl-N-((1R,3S,5S)-8-((((S)-1- 437.00 0.104620.55489 methylpiperidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9775-cyclopropyl-N-((1R,3r,5S)-8-((3-methyl- 450.00 0.10714 0.742373,8-diazabicyclo[3.2.1]octan-8-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9785-cyclopropyl-N-((1R,3r,5S)-8-((4-((2- 542.00 0.11701 1.32665phenylpropan-2-yl)amino)piperidin-1-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3- yl)isoxazole-3-carboxamide 9795-cyclopropyl-N-((1R,3S,5S)-8-((((S)-1- 423.00 0.11891 0.43627methylpyrrolidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9805-cyclopropyl-N-((2S,4S)-1-(((S)-2,4- 426.00 0.12021 0.69682dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 981 5-cyclopropyl-N-((1R,3R,5S)-8-(((R)-1-(2- 453.00 0.126580.4656 hydroxyethyl)piperidin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9825-cyclopropyl-N-((1R,3r,5S)-8-(((1- 423.00 0.1344 0.81946methylpyrrolidin-2-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9835-cyclopropyl-N-((2S,4S)-1-(((S)-2- 426.00 0.14182 0.93057ethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 984 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(((S)- 474.00 0.14191.84922 2-phenylpiperazin-1-yl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide 9855-cyclopropyl-N-((1R,3S,5S)-8-(((S)-1-(2- 453.00 0.15471 0.70778hydroxyethyl)piperidin-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9865-cyclopropyl-N-((1R,3r,5S)-8-((4-(((2- 511.00 0.1556 0.80727methoxyethyl)amino)methyl)phenyl)sulfonyl)- 8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide 987 N-((2S,4R)-1-((4-(2-aminopropan-2- 435.000.15781 0.77598 yl)phenyl)sulfonyl)-2-methylpiperidin-4-yl)-5-ethylisoxazole-3-carboxamide 9885-cyclopropyl-N-((1R,3r,5S)-8-((4-(2- 487.00 0.15808 1.67415(dimethylamino)propan-2- yl)phenyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9895-cyclopropyl-N-((2S,4S)-2-methyl-1- 411.00 0.17527 1.1575((piperidin-2-ylmethyl)sulfonyl)piperidin-4- yl)isoxazole-3-carboxamide990 5-cyclopropyl-N-((1R,3r,5S)-8-((8-(3,3,3- 532.00 0.18371 0.93509trifluoropropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide 9915-cyclopropyl-N-((2S,4S)-1-(((1- 453.00 0.18696 2.18933methylpiperidin-4-yl)methyl)sulfonyl)-2-propylpiperidin-4-yl)isoxazole-3- carboxamide 9925-cyclopropyl-N-((2S,4S)-1-(((2S,5S)-2,5- 426.00 0.18838 1.11838dimethylpiperazin-1-yl)sulfonyl)-2- methylpiperidin-4-yl)isoxazole-3-carboxamide 993 5-isobutyl-N-((1R,3r,5S)-8-(((1- 453.00 0.20637 2.77149methylpiperidin-4-yl)methyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3- carboxamide *IC₅₀ values are anaverage of n = 1 to n = 50

In another embodiment, a Compound of the Disclosure is a compound havingFormulae I-X, provided that the compound is not:

Structure Name

5-cyclopropyl-N-(piperidin-4- yl)isoxazole-3-carboxamide

N-(8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3- carboxamide

N-(1-(2-amino-2- oxoethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide

5-cyclopropyl-N-(1- (methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1- isobutyrylpiperidin-4-yl)isoxazole-3- carboxamide

N-(1-benzoylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

ethyl 4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1- carboxylate

5-cyclopropyl-N-(1-(furan-3- carbonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-((4- methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-tosylpiperidin- 4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-(2,6- dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-((4- acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamide

N-(1-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)piperidin-4-yl)-5-ethylisoxazole-3-carboxamide

5-ethyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamide

In some embodiments, the disclosure relates to pharmaceuticalcompositions comprising one or more of the following compounds:

Structure Name

5-cyclopropyl-N-(piperidin-4- yl)isoxazole-3-carboxamide

N-(8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3- carboxamide

N-(1-(2-amino-2- oxoethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide

5-cyclopropyl-N-(1- (methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1- isobutyrylpiperidin-4-yl)isoxazole-3- carboxamide

N-(1-benzoylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

ethyl 4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1- carboxylate

5-cyclopropyl-N-(1-(furan-3- carbonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-((4- methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-tosylpiperidin- 4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-(2,6- dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-((4- acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamide

N-(1-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)piperidin-4-yl)-5-ethylisoxazole-3-carboxamide

5-ethyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamideand a pharmaceutically acceptable carrier.

In some embodiments, the disclosure relates to a method of inhibitingSMYD proteins, such as SMYD3 or SMYD2, or both, in a subject, comprisingadministering to a subject in need thereof an effective amount of atleast one of the following compounds:

Structure Name

5-cyclopropyl-N-(piperidin-4- yl)isoxazole-3-carboxamide

N-(8-azabicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3- carboxamide

N-(1-(2-amino-2- oxoethyl)piperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide

5-cyclopropyl-N-(1- (methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1- isobutyrylpiperidin-4-yl)isoxazole-3- carboxamide

N-(1-benzoylpiperidin-4-yl)-5- cyclopropylisoxazole-3- carboxamide

ethyl 4-(5-cyclopropylisoxazole-3- carboxamido)piperidine-1- carboxylate

5-cyclopropyl-N-(1-(furan-3- carbonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-((4- methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-tosylpiperidin- 4-yl)isoxazole-3-carboxamide

5-cyclopropyl-N-(1-(2,6- dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3-carboxamide

N-(1-((4- acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3- carboxamide

5-cyclopropyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamide

N-(1-7,8-dihydro-5H-pyrano[4,3- d]pyrimidin-2-yl)piperidin-4-yl)-5-ethylisoxazole-3-carboxamide

5-ethyl-N-(1-(4-isopropyl-5- (pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3- carboxamide

Definitions

For the purpose of the present disclosure, the term “alkyl” as used byitself or as part of another group refers to a straight- orbranched-chain aliphatic hydrocarbon containing one to twelve carbonatoms (i.e., C₁₋₁₂ alkyl) or the number of carbon atoms designated(i.e., a C₁ alkyl such as methyl, a C₂ alkyl such as ethyl, a C₃ alkylsuch as propyl or isopropyl, etc.). In one embodiment, the alkyl groupis chosen from a straight chain C₁₋₁₀ alkyl group. In anotherembodiment, the alkyl group is chosen from a branched chain C₃₋₁₀ alkylgroup. In another embodiment, the alkyl group is chosen from a straightchain C₁₋₆ alkyl group. In another embodiment, the alkyl group is chosenfrom a branched chain C₃₋₆ alkyl group. In another embodiment, the alkylgroup is chosen from a straight chain C₁₋₄ alkyl group. In anotherembodiment, the alkyl group is chosen from a branched chain C₃₋₄ alkylgroup. In another embodiment, the alkyl group is chosen from a straightor branched chain C₃₋₄ alkyl group. In another embodiment, the alkylgroup is partially or completely deuterated, i.e., one or more hydrogenatoms of the alkyl group are replaced with deuterium atoms. Non-limitingexemplary C₁₋₁₀ alkyl groups include methyl (including —CD₃), ethyl,propyl, isopropyl, butyl, sec-butyl, tert-butyl, iso-butyl, 3-pentyl,hexyl, heptyl, octyl, nonyl, and decyl. Non-limiting exemplary C₁₋₄alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl,tert-butyl, and iso-butyl. Non-limiting exemplary C₁₋₄ groups includemethyl, ethyl, propyl, isopropyl, and tert-butyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkyl” as used by itself or as part of another group meansthat the alkyl as defined above is either unsubstituted or substitutedwith one, two, or three substituents independently chosen from nitro,haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,alkoxycarbonyl, and carboxyalkyl. In one embodiment, the alkyl is a C₁₋₄alkyl. In one embodiment, the optionally substituted alkyl issubstituted with two substituents. In another embodiment, the optionallysubstituted alkyl is substituted with one substituent. Non-limitingexemplary optionally substituted alkyl groups include —CH₂CH₂NO₂,—CH₂CH₂CO₂H, —CH₂CH₂SO₂CH₃, —CH₂CH₂COPh, and —CH₂C₆H₁₁.

For the purpose of the present disclosure, the term “cycloalkyl” as usedby itself or as part of another group refers to saturated and partiallyunsaturated (containing one or two double bonds) cyclic aliphatichydrocarbons containing one to three rings having from three to twelvecarbon atoms (i.e., C₃₋₁₂ cycloalkyl) or the number of carbonsdesignated. In one embodiment, the cycloalkyl group has two rings. Inone embodiment, the cycloalkyl group has one ring. In anotherembodiment, the cycloalkyl group is chosen from a C₃₋₈ cycloalkyl group.In another embodiment, the cycloalkyl group is chosen from a C₃₋₆cycloalkyl group. Non-limiting exemplary cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, andspiro[3.3]heptane.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkyl” as used by itself or as part of another groupmeans that the cycloalkyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy,aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido,alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido,guanidino, carboxy, carboxyalkyl, alkyl, optionally substitutedcycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkylamino, (cyano)alkyl, (carboxamido)alkyl,mercaptoalkyl, (heterocyclo)alkyl, or (heteroaryl)alkyl. In oneembodiment, the optionally substituted cycloalkyl is substituted withone, two, or three substituents independently chosen from halo, nitro,cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl,hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, or(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkyl is substituted with two substituents. In another embodiment,the optionally substituted cycloalkyl is substituted with onesubstituent. In one embodiment, the optionally substituted cycloalkyl issubstituted with at least one amino, alkylamino, or dialkylamino group.The term “amino-substituted cycloalkyl” as used by itself or as part ofanother group means that the optionally substituted cycloalkyl asdefined above is substituted with at least one amino group. In oneembodiment, the amino-substituted cycloalkyl is an amino-substitutedcyclohexyl group. Non-limiting exemplary optionally substitutedcycloalkyl groups include:

For the purpose of the present disclosure, the term “cycloalkenyl” asused by itself or part of another group refers to a partiallyunsaturated cycloalkyl group as defined above. In one embodiment, thecycloalkenyl has one carbon-to-carbon double bond. In anotherembodiment, the cycloalkenyl group is chosen from a C₄₋₈ cycloalkenylgroup. Exemplary cycloalkenyl groups include cyclopentenyl andcyclohexenyl.

For the purpose of the present disclosure, the term “optionallysubstituted cycloalkenyl” as used by itself or as part of another groupmeans that the cycloalkenyl as defined above is either unsubstituted orsubstituted with one, two, or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,aralkylamino, heteroalkyl, haloalkyl, monohydroxyalkyl, dihydroxyalkyl,alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substitutedcycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkenyl is substituted with one, two, or three substituentsindependently chosen from halo, nitro, cyano, hydroxy, amino,alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl,alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido,sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substitutedcycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedcycloalkenyl is substituted with two substituents. In anotherembodiment, the optionally substituted cycloalkenyl is substituted withone substituent. In another embodiment, the cycloalkenyl isunsubstituted.

For the purpose of the present disclosure, the term “alkenyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one, two or three carbon-to-carbon double bonds. In oneembodiment, the alkenyl group is chosen from a C₂₋₆ alkenyl group. Inanother embodiment, the alkenyl group is chosen from a C₂₋₄ alkenylgroup. Non-limiting exemplary alkenyl groups include ethenyl, propenyl,isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

For the purpose of the present disclosure, the term “optionallysubstituted alkenyl” as used herein by itself or as part of anothergroup means the alkenyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclo.

For the purpose of the present disclosure, the term “alkynyl” as used byitself or as part of another group refers to an alkyl group as definedabove containing one to three carbon-to-carbon triple bonds. In oneembodiment, the alkynyl has one carbon-to-carbon triple bond. In oneembodiment, the alkynyl group is chosen from a C₂₋₆ alkynyl group. Inanother embodiment, the alkynyl group is chosen from a C₂₋₄ alkynylgroup. Non-limiting exemplary alkynyl groups include ethynyl, propynyl,butynyl, 2-butynyl, pentynyl, and hexynyl groups.

For the purpose of the present disclosure, the term “optionallysubstituted alkynyl” as used herein by itself or as part of anothergroup means the alkynyl as defined above is either unsubstituted orsubstituted with one, two or three substituents independently chosenfrom halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.

For the purpose of the present disclosure, the term “haloalkyl” as usedby itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine, chlorine, bromine and/or iodineatoms. In one embodiment, the alkyl group is substituted by one, two, orthree fluorine and/or chlorine atoms. In another embodiment, thehaloalkyl group is chosen from a C₁₋₄ haloalkyl group. Non-limitingexemplary haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, andtrichloromethyl groups.

For the purpose of the present disclosure, the term “fluoroalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted by one or more fluorine atoms. In one embodiment, the alkylgroup is substituted by one, two, or three fluorine atoms. In anotherembodiment, the fluoroalkyl group is chosen from a C₁₋₄ fluoroalkylgroup. Non-limiting exemplary fluoroalkyl groups include fluoromethyl,difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl,2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and4,4,4-trifluorobutyl.

For the purpose of the present disclosure, the term “hydroxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more, e.g., one, two, or three, hydroxy groups.In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group,i.e., substituted with one hydroxy group. In another embodiment, thehydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with twohydroxy groups. In another embodiment, the hydroxyalkyl group is chosenfrom a C₁₋₄ hydroxyalkyl group. Non-limiting exemplary hydroxyalkylgroups include hydroxymethyl, hydroxyethyl, hydroxypropyl andhydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl,1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl,4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2-yl.

For the purpose of the present disclosure, the term “alkoxy” as used byitself or as part of another group refers to an optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted alkenylor optionally substituted alkynyl attached to a terminal oxygen atom. Inone embodiment, the alkoxy group is chosen from a C₁₋₄ alkoxy group. Inanother embodiment, the alkoxy group is chosen from a C₁₋₄ alkylattached to a terminal oxygen atom, e.g., methoxy, ethoxy, andtert-butoxy.

For the purpose of the present disclosure, the term “alkylthio” as usedby itself or as part of another group refers to a sulfur atomsubstituted by an optionally substituted alkyl group. In one embodiment,the alkylthio group is chosen from a C₁₋₄ alkylthio group. Non-limitingexemplary alkylthio groups include —SCH₃, and —SCH₂CH₃.

For the purpose of the present disclosure, the term “alkoxyalkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an alkoxy group. Non-limiting exemplary alkoxyalkylgroups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl,ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl,iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl,tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, andpentyloxymethyl.

For the purpose of the present disclosure, the term “haloalkoxy” as usedby itself or as part of another group refers to a haloalkyl attached toa terminal oxygen atom. Non-limiting exemplary haloalkoxy groups includefluoromethoxy, difluoromethoxy, trifluoromethoxy, and2,2,2-trifluoroethoxy.

For the purpose of the present disclosure, the term “heteroalkyl” asused by itself or part of another group refers to a stable straight orbranched chain hydrocarbon radical containing 1 to 10 carbon atoms andat least two heteroatoms, which can be the same or different, selectedfrom O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) canoptionally be oxidized; and/or 2) the nitrogen atom(s) can optionally bequaternized. The heteroatoms can be placed at any interior position ofthe heteroalkyl group or at a position at which the heteroalkyl group isattached to the remainder of the molecule.

In one embodiment, the heteroalkyl group contains two oxygen atoms. Inone embodiment, the heteroalkyl contains one oxygen and one nitrogenatom. In one embodiment, the heteroalkyl contains two nitrogen atoms.Non-limiting exemplary heteroalkyl groups include —CH₂OCH₂CH₂OCH₃,—OCH₂CH₂OCH₂CH₂OCH₃, —CH₂NHCH₂CH₂OCH₂, —OCH₂CH₂NH₂, —NHCH₂CH₂N(H)CH₃,—CH₂CH₂CH₂N(H)CH₂CH₂NH₂, —CH₂CH₂CH₂N(H)CH₂CH₂N(H)CH₃, —NHCH₂CH₂OCH₃,—N(CH₃)CH₂CH₂CH₂OCH₃, and —OCH₂CH₂OCH₃.

For the purpose of the present disclosure, the term “aryl” as used byitself or as part of another group refers to a monocyclic or bicyclicaromatic ring system having from six to fourteen carbon atoms (i.e.,C₆₋₁₄ aryl). Non-limiting exemplary aryl groups include phenyl(abbreviated as “Ph”), naphthyl, phenanthryl, anthracyl, indenyl,azulenyl, biphenyl, biphenylenyl, and fluorenyl groups. In oneembodiment, the aryl group is chosen from phenyl or naphthyl. In oneembodiment, the aryl group is phenyl.

For the purpose of the present disclosure, the term “optionallysubstituted aryl” as used herein by itself or as part of another groupmeans that the aryl as defined above is either unsubstituted orsubstituted with one to five substituents independently selected fromthe group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl,alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(cycloalkylamino)alkyl, (C₁₋₄ haloalkoxy)alkyl, (heteroaryl)alkyl,—N(R⁴³)(R⁴⁴), and —N(H)C(═O)—R⁴⁵, wherein R⁴³ is hydrogen or C₁₋₄ alkyl;R⁴⁴ is alkoxyalkyl, (heterocyclo)alkyl, (amino)alkyl, (alkylamino)alkyl,or (dialkylamino)alkyl; and R⁴⁵ is alkyl, optionally substituted aryl oroptionally substituted heteroaryl. In one embodiment, the optionallysubstituted aryl is substituted with one to five substituentsindependently selected from the group consisting of halo, nitro, cyano,hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl,alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy,alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl,alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl,alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mereaptoalkyl, (heterocyclo)alkyl,(cycloalkylamino)alkyl, (C₁₋₄ haloalkoxy)alkyl, (heteroaryl)alkyl,—N(R⁴³)(R⁴⁴), and —N(H)C(═O)—R⁴⁵. In one embodiment, the optionallysubstituted aryl is an optionally substituted phenyl. In one embodiment,the optionally substituted phenyl has four substituents. In anotherembodiment, the optionally substituted phenyl has three substituents. Inanother embodiment, the optionally substituted phenyl has twosubstituents. In another embodiment, the optionally substituted phenylhas one substituent. In another embodiment, the optionally substitutedphenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl,(alkylamino)alkyl, or (dialkylamino)alkyl substituent. The term“(amino)alkyl-substituted phenyl” as used by itself or as part ofanother group means that the optionally substituted phenyl as definedabove is substituted with at least one (amino)alkyl group. Non-limitingexemplary substituted aryl groups include 2-methylphenyl,2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl,3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl,4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl,4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl,3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di-methoxyphenyl,3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl,2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl,2-phenylpropan-2-amine,

The term optionally substituted aryl is meant to include groups havingfused optionally substituted cycloalkyl and fused optionally substitutedheterocyclo rings. Examples include:

For the purpose of the present disclosure, the term “aryloxy” as used byitself or as part of another group refers to an optionally substitutedaryl attached to a terminal oxygen atom. A non-limiting exemplaryaryloxy group is PhO—.

For the purpose of the present disclosure, the term “heteroaryloxy” asused by itself or as part of another group refers to an optionallysubstituted heteroaryl attached to a terminal oxygen atom.

For the purpose of the present disclosure, the term “aralkyloxy” or“arylalkyloxy” as used by itself or as part of another group refers toan aralkyl group attached to a terminal oxygen atom. A non-limitingexemplary aralkyloxy group is PhCH₂O—.

For the purpose of the present disclosure, the term “heteroaryl” or“heteroaromatic” refers to monocyclic and bicyclic aromatic ring systemshaving 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl) and 1,2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen orsulfur. In one embodiment, the heteroaryl has three heteroatoms. Inanother embodiment, the heteroaryl has two heteroatoms. In anotherembodiment, the heteroaryl has one heteroatom. In another embodiment,the heteroaryl is a 5- to 10-membered heteroaryl. In another embodiment,the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroarylhaving four carbon atoms and one sulfur atom. In another embodiment, theheteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroarylhaving five carbon atoms and one nitrogen atom. Non-limiting exemplaryheteroaryl groups include thienyl, benzo[b]thienyl,naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl,isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl,isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl,quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl,phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl,thiazolyl, isothiazolyl, phenothiazolyl, isoxazolyl, furazanyl, andphenoxazinyl. In one embodiment, the heteroaryl is chosen from thienyl(e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl),pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g.,2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g.,1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g.,pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g.,pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.,thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g.,isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g.,oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl) and isoxazolyl (e.g.,isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl). The term “heteroaryl”is also meant to include possible N-oxides. Exemplary N-oxides includepyridyl N-oxide.

For the purpose of the present disclosure, the term “optionallysubstituted heteroaryl” as used by itself or as part of another groupmeans that the heteroaryl as defined above is either unsubstituted orsubstituted with one to four substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl,alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), or —N(H)C(═O)—R⁴⁵, wherein R⁴³ ishydrogen or C₁₋₄ alkyl; R⁴⁴ is alkoxyalkyl, (heterocyclo)alkyl,(amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl; and R⁴⁵ isalkyl, optionally substituted aryl, or optionally substitutedheteroaryl. In another embodiment, the optionally substituted heteroarylis substituted with one to four substituents, e.g., one or twosubstituents, independently chosen from halo, nitro, cyano, hydroxy,amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy,haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido,sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl,ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substitutedcycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl,(heteroaryl)alkyl, —N(R⁴³)(R⁴⁴), or —N(H)C(═O)—R⁴⁵. In one embodiment,the optionally substituted heteroaryl has one substituent. In oneembodiment, the substituent is amino, alkylamino, dialkylamino,(amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl,(heterocyclo)alkyl, —N(R⁴³)(R⁴⁴), or —N(H)C(═O)—R⁴⁵. In one embodiment,the optionally substituted is an optionally substituted pyridyl, i.e.,2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can besubstituted.

For the purpose of the present disclosure, the term “heterocycle” or“heterocyclo” as used by itself or as part of another group refers tosaturated and partially unsaturated (e.g., containing one or two doublebonds) cyclic groups containing one, two, or three rings having fromthree to fourteen ring members (i.e., a 3- to 14-membered heterocyclo)and at least one heteroatom. Each heteroatom is independently selectedfrom the group consisting of oxygen, sulfur, including sulfoxide andsulfone, and/or nitrogen atoms, which can be quaternized. The term“heterocyclo” is meant to include cyclic ureido groups such asimidazolidinyl-2-one, cyclic amide groups such as β-lactam, γ-lactam,δ-lactam and ε-lactam, and cyclic carbamate groups such asoxazolidinyl-2-one. The term “heterocyclo” is also meant to includegroups having fused optionally substituted aryl groups, e.g., indolinyl,indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one. In one embodiment, theheterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclicgroup containing one ring and one or two oxygen and/or nitrogen atoms.In one embodiment, the heterocyclo group is chosen from a 5- or6-membered cyclic group containing one ring and one or two nitrogenatoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-,10-, 11-, or 12-membered cyclic group containing two rings and one ortwo nitrogen atoms. The heterocyclo can be optionally linked to the restof the molecule through a carbon or nitrogen atom. Non-limitingexemplary heterocyclo groups include 2-oxopyrrolidin-3-yl,2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl,8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane,6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one,1,3-dihydro-2H-benzo[d]imidazol-2-one.

For the purpose of the present disclosure, the term “optionallysubstituted heterocyclo” as used herein by itself or part of anothergroup means the heterocyclo as defined above is either unsubstituted orsubstituted with one to four substituents independently selected fromthe group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino,dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl,alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio,carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl,arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl,optionally substituted cycloalkyl, alkenyl, alkynyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkylamino,(cyano)alkyl, (carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. Substitution may occur on any available carbon ornitrogen atom, and may form a spirocycle. In another embodiment, theoptionally substituted heterocyclo is substituted with one to foursubstituents independently selected from the group consisting of halo,nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino,haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl,aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl,arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy,carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,(alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl,(carboxamido)alkyl, mercaptoalkyl, (heterocyclo)alkyl, and(heteroaryl)alkyl. In one embodiment, the optionally substitutedheterocyclo is substituted with at least one amino, alkylamino, ordialkylamino group. The term “amino-substituted heterocyclo” as used byitself or as part of another group means that the optionally substitutedheterocyclo as defined above is substituted with at least one aminogroup. Likewise, the term “alkylamino-substituted heterocyclo” as usedby itself or as part of another group means that the optionallysubstituted heterocyclo as defined above is substituted with at leastone alkylamino group. In one embodiment, the amino-substituted oralkylamino-substituted heterocyclo is an amino-substituted oralkylamino-substituted piperidine. Non-limiting exemplary optionallysubstituted heterocyclo groups include:

For the purpose of the present disclosure, the term “amino” as used byitself or as part of another group refers to —NH₂.

For the purpose of the present disclosure, the term “alkylamino” as usedby itself or as part of another group refers to —NHR²², wherein R²² isC₁₋₆ alkyl. In one embodiment, R²² is C₁₋₄ alkyl. Non-limiting exemplaryalkylamino groups include —N(H)CH₃ and —N(H)CH₂CH₃.

For the purpose of the present disclosure, the term “dialkylamino” asused by itself or as part of another group refers to —NR^(23a)R^(23b),wherein R^(23a) and R^(23b) are each independently C₁₋₆ alkyl. In oneembodiment, R^(23a) and R^(23b) are each independently C₁₋₄ alkyl.Non-limiting exemplary dialkylamino groups include —N(CH₃)₂ and—N(CH₃)CH₂CH(CH₃)₂.

For the purpose of the present disclosure, the term “hydroxyalkylamino”as used by itself or as part of another group refers to —NHR²⁴, whereinR²⁴ is hydroxyalkyl.

For the purpose of the present disclosure, the term “cycloalkylamino” asused by itself or as part of another group refers to —NR^(25a)R^(25b)wherein R^(25a) is optionally substituted cycloalkyl and R^(25b) ishydrogen or C₁₋₄ alkyl.

For the purpose of the present disclosure, the term “aralkylamino” asused by itself or as part of another group refers to —NR^(26a)R^(26b),wherein R^(26a) is aralkyl and R^(26b) is hydrogen or C₁₋₄ alkyl.Non-limiting exemplary aralkylamino groups include —N(H)CH₂Ph,—N(H)CHPh₂, and —N(CH₃)CH₂Ph.

For the purpose of the present disclosure, the term“(cycloalkyl)alkylamino” as used by itself or as part of another grouprefers to —NR^(26c)R^(26d) wherein R^(26a) is (cycloalkyl)alkyl andR^(26d) is hydrogen or C₁₋₄ alkyl. Non-limiting exemplary(cycloalkyl)alkylamino groups include:

For the purpose of the present disclosure, the term“(heterocyclo)alkylamino” as used by itself or as part of another grouprefers to —NR^(26e)R^(26f), wherein R^(26e) is (heterocyclo)alkyl andR^(26f) is hydrogen or C₁₋₄ alkyl. Non-limiting exemplary(heterocyclo)alkylamino groups include:

For the purpose of the present disclosure, the term “(amino)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with an amino group. In one embodiment, the alkyl is a C₁₋₄alkyl. Non-limiting exemplary (amino)alkyl groups include —CH₂NH₂,—C(CH₃)NH₂, —C(NH₂)(H)CH₃, —CH₂CH₂NH₂, —CH₂C(NH₂)(H)CH₃, —CH₂CH₂CH₂NH₂,—CH₂CH₂CH₂CH₂NH₂, and —CH₂C(CH₃)₂CH₂NH₂.

For the purpose of the present disclosure, the term “(alkylamino)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with an alkylamino group. In one embodiment, the alkyl is aC₁₋₄ alkyl. A non-limiting exemplary (alkylamino)alkyl group is—CH₂CH₂N(H)CH₃.

For the purpose of the present disclosure, the term“(dialkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a dialkylamino group. In oneembodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary(dialkylamino)alkyl groups are —CH₂CH₂N(CH₃)₂.

For the purpose of the present disclosure, the term“(cycloalkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted by a cycloalkylamino group. In oneembodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary(cycloalkylamino)alkyl groups include —CH₂N(H)cyclopropyl,—CH₂N(H)cyclobutyl, and —CH₂N(H)cyclohexyl.

For the purpose of the present disclosure, the term“[(cycloalkyl)alkylamino]alkyl” as used by itself or as part of anothergroup refers to an alkyl group substituted by a (cycloalkyl)alkylaminogroup. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limitingexemplary ([(cycloalkyl)alkylamino]alkyl groups include:

For the purpose of the present disclosure, the term“[(heterocyclo)alkylamino]alkyl” as used by itself or as part of anothergroup refers to an alkyl group substituted by a (heterocyclo)alkylaminogroup. In one embodiment, the alkyl is a C₁₋₄ alkyl. Non-limitingexemplary ([(heterocyclo)alkylamino]alkyl groups include:

For the purpose of the present disclosure, the term“(aralkylamino)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with an aralkylamino group. In oneembodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary(aralkylamino)alkyl groups include —CH₂CH₂CH₂N(H)CH₂Ph and—CH₂CH₂CH₂N(H)CH₂(4-CF₃-Ph).

For the purpose of the present disclosure, the term “(cyano)alkyl” asused by itself or as part of another group refers to an alkyl groupsubstituted with one or more cyano, e.g., —CN, groups. In oneembodiment, the alkyl is a C₁₋₄ alkyl. Non-limiting exemplary(cyano)alkyl groups include —CH₂CH₂CN, —CH₂CH₂CH₂CN, and—CH₂CH₂CH₂CH₂CN.

For the purpose of the present disclosure, the term“(amino)(hydroxy)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with one amino, alkylamino, ordialkylamino group and one hydroxy group. In one embodiment, the alkylis a C₁₋₆ alkyl. In another embodiment, the alkyl is a C₁₋₄ alkyl.Non-limiting exemplary (amino)(hydroxy)alkyl groups include:

For the purpose of the present disclosure, the term “(amino)(aryl)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one amino, alkylamino, or dialkylamino group and oneoptionally substituted aryl group. In one embodiment, the alkyl is aC₁₋₆ alkyl. In one embodiment, the optionally substituted aryl group isan optionally substituted phenyl. Non-limiting exemplary(amino)(aryl)alkyl groups include:

For the purpose of the present disclosure, the term “(cycloalkyl)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one optionally substituted cycloalkyl group. In oneembodiment, the alkyl is a C₁₋₄ alkyl. In one embodiment, the cycloalkylis a C₃₋₆ cycloalkyl. In one embodiment, the optionally substitutedcycloalkyl group is substituted with an amino or (amino)alkyl group.Non-limiting exemplary (cycloalkyl)alkyl groups include:

For the purpose of the present disclosure, the term“(hydroxy)(aryl)alkyl” as used by itself or as part of another grouprefers to an alkyl group substituted with one hydroxy group and oneoptionally substituted aryl group. In one embodiment, the alkyl is aC₁₋₆ alkyl. In one embodiment, the optionally substituted aryl group isan optionally substituted phenyl. Non-limiting exemplary(hydroxy)(aryl)alkyl groups include:

For the purpose of the present disclosure, the term “carboxamido” asused by itself or as part of another group refers to a radical offormula —C(═O)NR^(26a)R^(26b), wherein R^(26a) and R^(26b) are eachindependently hydrogen, optionally substituted alkyl, optionallysubstituted aryl, or optionally substituted heteroaryl, or R^(26a) andR^(26b) taken together with the nitrogen to which they are attached froma 3- to 8-membered heterocyclo group. In one embodiment, R^(26a) andR^(26b) are each independently hydrogen or optionally substituted alkyl.Non-limiting exemplary carboxamido groups include —CONH₂, —CON(H)CH₃,CON(CH₃)₂, and —CON(H)Ph.

For the purpose of the present disclosure, the term “(carboxamido)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with a carboxamido group. Non-limiting exemplary(carboxamido)alkyl groups include —CH₂CONH₂, —C(H)CH₃—CONH₂, and—CH₂CON(H)CH₃.

For the purpose of the present disclosure, the term “sulfonamido” asused by itself or as part of another group refers to a radical of theformula —SO₂NR^(27a)R^(27b), wherein R^(27a) and R^(27b) are eachindependently hydrogen, optionally substituted alkyl, or optionallysubstituted aryl, or R^(27a) and R^(27b) taken together with thenitrogen to which they are attached from a 3- to 8-membered heterocyclogroup. Non-limiting exemplary sulfonamido groups include —SO₂NH₂,—SO₂N(H)CH₃, and —SO₂N(H)Ph.

For the purpose of the present disclosure, the term “alkylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkyl group. A non-limiting exemplaryalkylcarbonyl group is —COCH₃.

For the purpose of the present disclosure, the term “arylcarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an optionally substituted aryl group. Anon-limiting exemplary arylcarbonyl group is —COPh.

For the purpose of the present disclosure, the term “alkylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted alkyl groups. A non-limiting exemplary alkylsulfonyl groupis —SO₂CH₃.

For the purpose of the present disclosure, the term “arylsulfonyl” asused by itself or as part of another group refers to a sulfonyl group,i.e., —SO₂—, substituted by any of the above-mentioned optionallysubstituted aryl groups. A non-limiting exemplary arylsulfonyl group is—SO₂Ph.

For the purpose of the present disclosure, the term “mercaptoalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted by a —SH group.

For the purpose of the present disclosure, the term “carboxy” as used byitself or as part of another group refers to a radical of the formula—COOH.

For the purpose of the present disclosure, the term “carboxyalkyl” asused by itself or as part of another group refers to any of theabove-mentioned alkyl groups substituted with a —COOH. A non-limitingexemplary carboxyalkyl group is —CH₂CO₂H.

For the purpose of the present disclosure, the term “alkoxycarbonyl” asused by itself or as part of another group refers to a carbonyl group,i.e., —C(═O)—, substituted by an alkoxy group. In one embodiment, thealkoxy group is a C₁₋₄ alkoxy. Non-limiting exemplary alkoxycarbonylgroups are —CO₂Me and —CO₂Et.

For the purpose of the present disclosure, the term “aralkyl” or“arylalkyl” as used by itself or as part of another group refers to analkyl group substituted with one, two, or three optionally substitutedaryl groups. In one embodiment, the aralkyl group is a C₁₋₄ alkylsubstituted with one optionally substituted aryl group. Non-limitingexemplary aralkyl groups include benzyl, phenethyl, —CHPh₂,—CH₂(4-OH-Ph), and —CH(4-F-Ph)₂.

For the purpose of the present disclosure, the term “ureido” as used byitself or as part of another group refers to a radical of the formula—NR^(30a)—C(═O)—NR^(30b)R^(30c), wherein R^(30a) is hydrogen, alkyl, oroptionally substituted aryl, and R^(30b) and R^(30c) are eachindependently hydrogen, alkyl, or optionally substituted aryl, orR^(30b) and R^(30c) taken together with the nitrogen to which they areattached form a 4- to 8-membered heterocyclo group. Non-limitingexemplary ureido groups include —NH—C(C═O)—NH₂ and —NH—C(C═O)—NHCH₃.

For the purpose of the present disclosure, the term “guanidino” as usedby itself or as part of another group refers to a radical of the formula—NR^(28a)—C(NR²⁹)—NR^(28b)R^(28c), wherein R^(28a), R^(28b), and R^(28c)are each independently hydrogen, alkyl, or optionally substituted aryl,and R²⁹ is hydrogen, alkyl, cyano, alkylsulfonyl, alkylcarbonyl,carboxamido, or sulfonamido. Non-limiting exemplary guanidino groupsinclude —NH—C(C═NH)—NH₂, —NH—C(C═NCN)—NH₂, and —NH—C(C═NH)—NHCH₃.

For the purpose of the present disclosure, the term “(heterocyclo)alkyl”as used by itself or as part of another group refers to an alkyl groupsubstituted with one, two, or three optionally substituted heterocyclogroups. In one embodiment, the (heterocyclo)alkyl is a C₁₋₄ alkylsubstituted with one optionally substituted heterocyclo group. Theheterocyclo can be linked to the alkyl group through a carbon ornitrogen atom. Non-limiting exemplary (heterocyclo)alkyl groups include:

For the purpose of the present disclosure, the term “(heteroaryl)alkyl”or “heteroaralkyl” as used by itself or as part of another group refersto an alkyl group substituted with one, two, or three optionallysubstituted heteroaryl groups. In one embodiment, the (heteroaryl)alkylgroup is a C₁₋₄ alkyl substituted with one optionally substitutedheteroaryl group. Non-limiting exemplary (heteroaryl)alkyl groupsinclude:

For the purpose of the present disclosure, the term “alkylcarbonylamino”as used by itself or as part of another group refers to an alkylcarbonylgroup attached to an amino. A non-limiting exemplary alkylcarbonylaminogroup is —NHCOCH₃.

For the purpose of the present disclosure, the term “C₁₋₄ bridge” refersto a —CH₂—, —(CH₂)₂—, —(CH₂)₃—, or —(CH₂)₄— group that joins two carbonatoms of a piperidine to form an azabicyclo group. For example, inFormula I, R^(3a) and R^(4a) of B can be taken together to form a6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane,9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group. Eachmethylene unit of the C₁₋₄ bridge can be optionally substituted with oneor two substituents independently selected from the group consisting ofC₁₋₄ alkyl and halo.

The present disclosure encompasses any of the Compounds of theDisclosure being isotopically-labelled (i.e., radiolabeled) by havingone or more atoms replaced by an atom having a different atomic mass ormass number. Examples of isotopes that can be incorporated into thedisclosed compounds include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorous, fluorine and chlorine, such as ²H (or deuterium(D)), ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl,respectively, e.g., ³H, ¹¹C, and ¹⁴C. In one embodiment, provided is acomposition wherein substantially all of the atoms at a position withinthe Compound of the Disclosure are replaced by an atom having adifferent atomic mass or mass number. In another embodiment, provided isa composition wherein a portion of the atoms at a position within theCompound of the disclosure are replaced, i.e., the Compound of theDisclosure is enriched at a position with an atom having a differentatomic mass or mass number.” Isotopically-labelled Compounds of theDisclosure can be prepared by methods known in the art.

Compounds of the Disclosure may contain one or more asymmetric centersand may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. The present disclosure is meant to encompass theuse of all such possible forms, as well as their racemic and resolvedforms and mixtures thereof. The individual enantiomers can be separatedaccording to methods known in the art in view of the present disclosure.When the compounds described herein contain olefinic double bonds orother centers of geometric asymmetry, and unless specified otherwise, itis intended that they include both E and Z geometric isomers. Alltautomers are intended to be encompassed by the present disclosure aswell.

As used herein, the term “stereoisomers” is a general term for allisomers of individual molecules that differ only in the orientation oftheir atoms in space. It includes enantiomers and isomers of compoundswith more than one chiral center that are not mirror images of oneanother (diastereomers).

The term “chiral center” or “asymmetric carbon atom” refers to a carbonatom to which four different groups are attached.

The terms “enantiomer” and “enantiomeric” refer to a molecule thatcannot be superimposed on its mirror image and hence is optically activewherein the enantiomer rotates the plane of polarized light in onedirection and its mirror image compound rotates the plane of polarizedlight in the opposite direction.

The term “racemic” refers to a mixture of equal parts of enantiomers andwhich mixture is optically inactive. In one embodiment, Compounds of theDisclosure are racemic.

The term “absolute configuration” refers to the spatial arrangement ofthe atoms of a chiral molecular entity (or group) and its stereochemicaldescription, e.g., R or S.

The stereochemical terms and conventions used in the specification aremeant to be consistent with those described in Pure & Appl. Chem 68:2193(1996), unless otherwise indicated.

The term “enantiomeric excess” or “ee” refers to a measure for how muchof one enantiomer is present compared to the other. For a mixture of Rand S enantiomers, the percent enantiomeric excess is defined as|R−S|*100, where R and S are the respective mole or weight fractions ofenantiomers in a mixture such that R+S=1. With knowledge of the opticalrotation of a chiral substance, the percent enantiomeric excess isdefined as ([α]_(obs)/[α]_(max))*100, where [α]_(obs) is the opticalrotation of the mixture of enantiomers and [α]_(max) is the opticalrotation of the pure enantiomer. Determination of enantiomeric excess ispossible using a variety of analytical techniques, including NMRspectroscopy, chiral column chromatography or optical polarimetry.

The terms “enantiomerically pure” or “enantiopure” refer to a sample ofa chiral substance all of whose molecules (within the limits ofdetection) have the same chirality sense. In one embodiment, Compoundsof the Disclosure are enantiomerically pure.

The terms “enantiomerically enriched” or “enantioenriched” refer to asample of a chiral substance whose enantiomeric ratio is greater than50:50. In one embodiment, Compounds of the Disclosure areenantiomerically enriched, e.g., the enantiomeric ratio is about 60:40or greater, about 70:30 or greater, about 80:20 or greater, about 90:10or greater, about 95:5 or greater, about 98:2 or greater, or about 99:1or greater. Enantiomerically enriched compounds may be enantiomericallypure.

The terms “a” and “an” refer to one or more.

The term “about,” as used herein, includes the recited number ±10%.Thus, “about 10” means 9 to 11.

The present disclosure encompasses the preparation and use of salts ofthe Compounds of the Disclosure, including non-toxic pharmaceuticallyacceptable salts. Examples of pharmaceutically acceptable addition saltsinclude inorganic and organic acid addition salts and basic salts. Thepharmaceutically acceptable salts include, but are not limited to, metalsalts such as sodium salt, potassium salt, cesium salt and the like;alkaline earth metals such as calcium salt, magnesium salt and the like;organic amine salts such as triethylamine salt, pyridine salt, picolinesalt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt and the like; inorganic acid saltssuch as hydrochloride, hydrobromide, phosphate, sulphate and the like;organic acid salts such as citrate, lactate, tartrate, maleate,fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate,oxalate, formate and the like; sulfonates such as methanesulfonate,benzenesulfonate, p-toluenesulfonate and the like; and amino acid saltssuch as arginate, asparginate, glutamate and the like. The term“pharmaceutically acceptable salt” as used herein, refers to any salt,e.g., obtained by reaction with an acid or a base, of a Compound of theDisclosure that is physiologically tolerated in the target patient(e.g., a mammal, e.g., a human).

Acid addition salts can be formed by mixing a solution of the particularCompound of the Disclosure with a solution of a pharmaceuticallyacceptable non-toxic acid such as hydrochloric acid, fumaric acid,maleic acid, succinic acid, acetic acid, citric acid, tartaric acid,carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or thelike. Basic salts can be formed by mixing a solution of the compound ofthe present disclosure with a solution of a pharmaceutically acceptablenon-toxic base such as sodium hydroxide, potassium hydroxide, cholinehydroxide, sodium carbonate and the like.

The present disclosure encompasses the preparation and use of solvatesof Compounds of the Disclosure. Solvates typically do not significantlyalter the physiological activity or toxicity of the compounds, and assuch may function as pharmacological equivalents. The term “solvate” asused herein is a combination, physical association and/or solvation of acompound of the present disclosure with a solvent molecule such as, e.g.a disolvate, monosolvate or hemisolvate, where the ratio of solventmolecule to compound of the present disclosure is about 2:1, about 1:1or about 1:2, respectively. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances, the solvate can be isolated, such as when one or moresolvent molecules are incorporated into the crystal lattice of acrystalline solid. Thus, “solvate” encompasses both solution-phase andisolatable solvates. Compounds of the Disclosure can be present assolvated forms with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that thedisclosure includes both solvated and unsolvated forms of Compounds ofthe Disclosure. One type of solvate is a hydrate. A “hydrate” relates toa particular subgroup of solvates where the solvent molecule is water.Solvates typically can function as pharmacological equivalents.Preparation of solvates is known in the art. See, for example, M. Cairaet al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes thepreparation of solvates of fluconazole with ethyl acetate and withwater. Similar preparation of solvates, hemisolvates, hydrates, and thelike are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech.,5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604(2001). A typical, non-limiting, process of preparing a solvate wouldinvolve dissolving a Compound of the Disclosure in a desired solvent(organic, water, or a mixture thereof) at temperatures above 20° C. toabout 25° C., then cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques such as infrared spectroscopy can be used toconfirm the presence of the solvent in a crystal of the solvate.

Since Compounds of the Disclosure are inhibitors of SMYD proteins, suchas SMYD3 and SMYD2, a number of diseases, conditions, or disordersmediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated byemploying these compounds. The present disclosure is thus directedgenerally to a method for treating a disease, condition, or disorderresponsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2,in an animal suffering from, or at risk of suffering from, the disorder,the method comprising administering to the animal an effective amount ofone or more Compounds of the Disclosure.

The present disclosure is further directed to a method of inhibitingSMYD proteins in an animal in need thereof, the method comprisingadministering to the animal a therapeutically effective amount of atleast one Compound of the Disclosure.

The present disclosure is further directed to a method of inhibitingSMYD3 in an animal in need thereof, the method comprising administeringto the animal a therapeutically effective amount of at least oneCompound of the Disclosure.

The present disclosure is further directed to a method of inhibitingSMYD2 in an animal in need thereof, the method comprising administeringto the animal a therapeutically effective amount of at least oneCompound of the Disclosure.

As used herein, the terms “treat,” “treating,” “treatment,” and the likerefer to eliminating, reducing, or ameliorating a disease or condition,and/or symptoms associated therewith. Although not precluded, treating adisease or condition does not require that the disease, condition, orsymptoms associated therewith be completely eliminated. As used herein,the terms “treat,” “treating,” “treatment,” and the like may include“prophylactic treatment,” which refers to reducing the probability ofredeveloping a disease or condition, or of a recurrence of apreviously-controlled disease or condition, in a subject who does nothave, but is at risk of or is susceptible to, redeveloping a disease orcondition or a recurrence of the disease or condition. The term “treat”and synonyms contemplate administering a therapeutically effectiveamount of a Compound of the Disclosure to an individual in need of suchtreatment.

Within the meaning of the disclosure, “treatment” also includes relapseprophylaxis or phase prophylaxis, as well as the treatment of acute orchronic signs, symptoms and/or malfunctions. The treatment can beorientated symptomatically, for example, to suppress symptoms. It can beeffected over a short period, be oriented over a medium term, or can bea long-term treatment, for example within the context of a maintenancetherapy.

The term “therapeutically effective amount” or “effective dose” as usedherein refers to an amount of the active ingredient(s) that is(are)sufficient, when administered by a method of the disclosure, toefficaciously deliver the active ingredient(s) for the treatment ofcondition or disease of interest to an individual in need thereof. Inthe case of a cancer or other proliferation disorder, thetherapeutically effective amount of the agent may reduce (i.e., retardto some extent and preferably stop) unwanted cellular proliferation;reduce the number of cancer cells; reduce the tumor size; inhibit (i.e.,retard to some extent and preferably stop) cancer cell infiltration intoperipheral organs; inhibit (i.e., retard to some extent and preferablystop) tumor metastasis; inhibit, to some extent, tumor growth; modulateprotein methylation in the target cells; and/or relieve, to some extent,one or more of the symptoms associated with the cancer. To the extentthe administered compound or composition prevents growth and/or killsexisting cancer cells, it may be cytostatic and/or cytotoxic.

The term “container” means any receptacle and closure therefore suitablefor storing, shipping, dispensing, and/or handling a pharmaceuticalproduct.

The term “insert” means information accompanying a pharmaceuticalproduct that provides a description of how to administer the product,along with the safety and efficacy data required to allow the physician,pharmacist, and patient to make an informed decision regarding use ofthe product. The package insert generally is regarded as the “label” fora pharmaceutical product.

The term “disease” or “condition” or “disorder” denotes disturbancesand/or anomalies that as a rule are regarded as being pathologicalconditions or functions, and that can manifest themselves in the form ofparticular signs, symptoms, and/or malfunctions. As demonstrated below,Compounds of the Disclosure inhibit SMYD proteins, such as SMYD3 andSMYD2 and can be used in treating diseases and conditions such asproliferative diseases, wherein inhibition of SMYD proteins, such asSMYD3 and SMYD2 provides a benefit.

In some embodiments, the Compounds of the Disclosure can be used totreat a “SMYD protein mediated disorder” (e.g., a SMYD3-mediateddisorder or a SMYD2-mediated disorder). A SMYD protein mediated disorderis any pathological condition in which a SMYD protein is know to play arole. In some embodiments, a SMYD-mediated disorder is a proliferativedisease.

In some embodiments inhibiting SMYD proteins, such as SMYD3 and SMYD2,is the inhibition of the activity of one or more activities of SMYDproteins such as SMYD3 and SMYD2. In some embodiments, the activity ofthe SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYDprotein such as SMYD3 or SMYD2 to transfer a methyl group to a targetprotein (e.g., histone). It should be appreciated that the activity ofthe one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibitedin vitro or in vivo. Exemplary levels of inhibition of the activity oneor more SMYD proteins such as SMYD3 and SMYD2 include at least 10%inhibition, at least 20% inhibition, at least 30% inhibition, at least40% inhibition, at least 50% inhibition, at least 60% inhibition, atleast 70% inhibition, at least 80% inhibition, at least 90% inhibition,and up to 100% inhibition.

The SMYD (SET and MYND domain) family of lysine methyltransferases(KMTs) plays pivotal roles in various cellular processes, including geneexpression regulation and DNA damage response. The family of human SMYDproteins consists of SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5. SMYD1, SMYD2,and SMYD3 share a high degree of sequence homology and, with theexception of SMYD5, human SMYD proteins harbor at least one C-terminaltetratrico peptide repeat (TPR) domain. (See e.g., Abu-Farha et al. JMol Cell Biol (2011) 3 (5) 301-308). The SMYD proteins have been foundto be linked to various cancers (See e.g., Hamamoto et al. Nat Cell.Biol. 2004, 6: 731-740), Hu et al. Canncer Research 2009, 4067-4072, andKomatsu et al. Carcinogenesis 2009, 301139-1146.)

SMYD3 is a protein methyltransferase found to be expressed at highlevels in a number of different cancers (Hamamoto, R., et al., Nat. CellBiol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulationof gene transcription and signal transduction pathways critical forsurvival of breast, liver, prostate and lung cancer cell lines(Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Hamamoto,R., et al., Cancer Sci., 97(2):113-8 (2006); Van Aller, G. S., et al.,Epigenetics, 7(4):340-3 (2012); Liu, C., et al., J. Natl. Cancer Inst.,105(22):1719-28 (2013); Mazur, P. K., et al., Nature, 510(7504):283-7(2014)).

Genetic knockdown of SMYD3 leads to a decrease in proliferation of avariety of cancer cell lines (Hamamoto, R., et al., Nat. Cell Biol.,6(8):731-40 (2004); Hamamoto, R., et al., Cancer Sci., 97(2):113-8(2006); Van Aller, G. S., et al., Epigenetics, 7(4):340-3 (2012); Liu,C., et al., J. Natl. Cancer Inst., 105(22):1719-28 (2013); Mazur, P. K.,et al., Nature, 510(7504):283-7 (2014)). Several studies employingRNAi-based technologies have shown that ablation of SMYD3 inhepatocellular carcinoma cell lines greatly reduces cell viability andthat its pro-survival role is dependent on its catalytic activity(Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller,G. S., et al., Epigenetics, 7(4):340-3 (2012)). Moreover, SMYD3 has alsobeen shown to be a critical mediator of transformation resulting fromgain of function mutations in the oncogene, KRAS for both pancreatic andlung adenocarcinoma in mouse models. The dependence of KRAS on SMYD3 wasalso shown to be dependent on its catalytic activity (Mazur, P. K., etal., Nature, 510(7504):283-7 (2014)). SMYD3 function has also beenimplicated in colorectal cancers and RNAi mediated knockdown of SMYD3has been shown to impair colorectal cell proliferation. (Peserico etal., Cell Physiol. 2015 Feb. 28. doi: 10.1002/jcp.24975. [Epub ahead ofprint]).

Furthermore, SMYD3 function has also been shown to play a role inimmunology and development. For instance, de Almeida reported that SMYD3plays a role in generation of inducible regulatory T cells (iTreg)cells. In a mouse model of respiratory syncytial virus (RSV) infection,a model in which iTreg cells have a critical role in regulating lungpathogenesis, SMYD3−/− mice demonstrated exacerbation of RSV-induceddisease related to enhanced proinflammatory responses and worsenedpathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015Feb. 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]). In addition, asto development, Proserpio et al. have shown the importance of SMYD3 inthe regulation of skeletal muscle atrophy (Proserpio et al. Genes Dev.2013 Jun. 1; 27(11):1299-312), while Fujii et al. have elucidated therole of SMYD3 in cardiac and skeletal muscle development (Fujii et al.PLoS One. 2011; 6(8): e23491).

SMYD2 (SET and MYND domain-containing protein 2) was first characterizedas protein that is a member of a sub-family of SET domain containingproteins which catalyze the site-specific transfer of methyl groups ontosubstrate proteins. SMYD2 was initially shown to have methyltransferaseactivity towards lysine 36 on histone H3 (H3K36) but has subsequentlybeen shown to have both histone and non-histone methyltrasferaseactivity.

SMYD2 has been implicated in the pathogenesis of multiple cancers. Ithas been shown to be over-expressed, compared to matched normal samples,in tumors of the breast, cervix, colon, kidney, liver, head and neck,skin, pancreas, ovary, esophagus and prostate, as well as hematologicmalignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a rolefor SMYD2 in the biology of these cancers. More specifically, studiesusing genetic knock-down of SMYD2 have demonstrated anti-proliferativeeffects in esophageal squamous cell carcinoma (ESCC), bladder carcinomaand cervical carcinoma cell lines. (See e.g., Komatsu et al.,Carcinogenesis 2009, 30, 1139, and Cho et al., Neoplasia. 2012 June;14(6):476-86). Moreover, high expression of SMYD2 has been shown to be apoor prognostic factor in both ESCC and pediatric ALL. (See e.g.,Komatsu et al. Br J Cancer. 2015 Jan. 20; 112(2):357-64, and Sakamoto etal., Leuk Res. 2014 April; 38(4):496-502). Recently, Nguyen et al., haveshown that a small molecule inhibitor of SMYD2 (LLY-507) inhibited theproliferation of several esophageal, liver and breast cancer cell linesin a dose-dependent manner. (Nguyen et al. J Biol Chem. 2015 Mar. 30.pii: jbc.M114.626861. [Epub ahead of print]).

SMYD2 has also been implicated in immunology. For instance, Xu et al.have shown that SMYD2 is a negative regulator of macrophage activationby suppressing Interleukin-6 and TNF-alpha production. (Xu et al., JBiol Chem. 2015 Feb. 27; 290(9):5414-23).

In one aspect, the present disclosure provides a method of treatingcancer in a patient comprising administering a therapeutically effectiveamount of a Compound of the Disclosure. While not being limited to aspecific mechanism, in some embodiments, Compounds of the Disclosure cantreat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2.Examples of treatable cancers include, but are not limited to, adrenalcancer, acinic cell carcinoma, acoustic neuroma, acral lentigiousmelanoma, acrospiroma, acute eosinophilic leukemia, acute erythroidleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia,acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma,adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor,adenosquamous carcinoma, adipose tissue neoplasm, adrenocorticalcarcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia,AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft partsarcoma, ameloblastic fibroma, anaplastic large cell lymphoma,anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoidtumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocyticleukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer,bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor,Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma insitu, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma,chondroma, chordoma, choriocarcinoma, choroid plexus papilloma,clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-celllymphoma, cervical cancer, colorectal cancer, Degos disease,desmoplastic small round cell tumor, diffuse large B-cell lymphoma,dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonalcarcinoma, endocrine gland neoplasm, endodermal sinus tumor,enteropathy-associated T-cell lymphoma, esophageal cancer, fetus infetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroidcancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor,gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumorof the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosiscerebri, glucagonoma, gonadoblastoma, granulosa cell tumor,gynandroblastoma, gallbladder cancer, gastric cancer, hairy cellleukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma,hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma,intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna,lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lungcancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma,acute lymphocytic leukemia, acute myelogeous leukemia, chroniclymphocytic leukemia, liver cancer, small cell lung cancer, non-smallcell lung cancer, MALT lymphoma, malignant fibrous histiocytoma,malignant peripheral nerve sheath tumor, malignant triton tumor, mantlecell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia,mediastinal germ cell tumor, medullary carcinoma of the breast,medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkelcell cancer, mesothelioma, metastatic urothelial carcinoma, mixedMullerian tumor, mucinous tumor, multiple myeloma, muscle tissueneoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma,nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma,neuroma, nodular melanoma, ocular cancer, oligoastrocytoma,oligodendroglioma, oncocytoma, optic nerve sheath meningioma, opticnerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor,papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma,pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma,polyembryoma, precursor T-lymphoblastic lymphoma, primary centralnervous system lymphoma, primary effusion lymphoma, preimary peritonealcancer, prostate cancer, pancreatic cancer, pharyngeal cancer,pseudomyxoma periotonei, renal cell carcinoma, renal medullarycarcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter'stransformation, rectal cancer, sarcoma, Schwannomatosis, seminoma,Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cellcarcinoma, skin cancer, small blue round cell tumors, small cellcarcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinaltumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovialsarcoma, Sezary's disease, small intestine cancer, squamous carcinoma,stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroidcancer, transitional cell carcinoma, throat cancer, urachal cancer,urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer,verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginalcancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms'tumor.

In another embodiment, the cancer is breast, cervix, colon, kidney,liver, head and neck, skin, pancreas, ovary, esophagus, or prostatecancer.

In another embodiment, the cancer is a hematologic malignancy such asacute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia(ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma(MCL).

In another embodiment, the cancer is esophageal squamous cell carcinoma(ESCC), bladder carcinoma, or cervical carcinoma.

In another embodiment, the cancer is a leukemia, for example a leukemiaselected from acute monocytic leukemia, acute myelogenous leukemia,chronic myelogenous leukemia, chronic lymphocytic leukemia and mixedlineage leukemia (MLL). In another embodiment the cancer is NUT-midlinecarcinoma. In another embodiment the cancer is multiple myeloma. Inanother embodiment the cancer is a lung cancer such as small cell lungcancer (SCLC). In another embodiment the cancer is a neuroblastoma. Inanother embodiment the cancer is Burkitt's lymphoma. In anotherembodiment the cancer is cervical cancer. In another embodiment thecancer is esophageal cancer. In another embodiment the cancer is ovariancancer. In another embodiment the cancer is colorectal cancer. Inanother embodiment, the cancer is prostate cancer. In anotherembodiment, the cancer is breast cancer.

In another embodiment, the present disclosure provides a therapeuticmethod of modulating protein methylation, gene expression, cellproliferation, cell differentiation and/or apoptosis in vivo in thecancers mentioned above by administering a therapeutically effectiveamount of a Compound of the Disclosure to a subject in need of suchtherapy.

Compounds of the Disclosure can be administered to a mammal in the formof a raw chemical without any other components present. Compounds of theDisclosure can also be administered to a mammal as part of apharmaceutical composition containing the compound combined with asuitable pharmaceutically acceptable carrier. Such a carrier can beselected from pharmaceutically acceptable excipients and auxiliaries.The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable vehicle” encompasses any of the standard pharmaceuticalcarriers, solvents, surfactants, or vehicles. Suitable pharmaceuticallyacceptable vehicles include aqueous vehicles and nonaqueous vehicles.Standard pharmaceutical carriers and their formulations are described inRemington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.,19th ed. 1995.

Pharmaceutical compositions within the scope of the present disclosureinclude all compositions where a Compound of the Disclosure is combinedwith one or more pharmaceutically acceptable carriers. In oneembodiment, the Compound of the Disclosure is present in the compositionin an amount that is effective to achieve its intended therapeuticpurpose. While individual needs may vary, a determination of optimalranges of effective amounts of each compound is within the skill of theart. Typically, a Compound of the Disclosure can be administered to amammal, e.g., a human, orally at a dose of from about 0.0025 to about1500 mg per kg body weight of the mammal, or an equivalent amount of apharmaceutically acceptable salt or solvate thereof, per day to treatthe particular disorder. A useful oral dose of a Compound of theDisclosure administered to a mammal is from about 0.0025 to about 50 mgper kg body weight of the mammal, or an equivalent amount of thepharmaceutically acceptable salt or solvate thereof. For intramuscularinjection, the dose is typically about one-half of the oral dose.

A unit oral dose may comprise from about 0.01 mg to about 1 g of theCompound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about50 mg, e.g., about 0.1 mg to about 10 mg, of the compound. The unit dosecan be administered one or more times daily, e.g., as one or moretablets or capsules, each containing from about 0.01 mg to about 1 g ofthe compound, or an equivalent amount of a pharmaceutically acceptablesalt or solvate thereof.

A pharmaceutical composition of the present disclosure can beadministered to any patient that may experience the beneficial effectsof a Compound of the Disclosure. Foremost among such patients aremammals, e.g., humans and companion animals, although the disclosure isnot intended to be so limited. In one embodiment, the patient is ahuman.

A pharmaceutical composition of the present disclosure can beadministered by any means that achieves its intended purpose. Forexample, administration can be by the oral, parenteral, subcutaneous,intravenous, intramuscular, intraperitoneal, transdermal, intranasal,transmucosal, rectal, intravaginal or buccal route, or by inhalation.The dosage administered and route of administration will vary, dependingupon the circumstances of the particular subject, and taking intoaccount such factors as age, gender, health, and weight of therecipient, condition or disorder to be treated, kind of concurrenttreatment, if any, frequency of treatment, and the nature of the effectdesired.

In one embodiment, a pharmaceutical composition of the presentdisclosure can be administered orally. In another embodiment, apharmaceutical composition of the present disclosure can be administeredorally and is formulated into tablets, dragees, capsules, or an oralliquid preparation. In one embodiment, the oral formulation comprisesextruded multiparticulates comprising the Compound of the Disclosure.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered rectally, and is formulated in suppositories.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by injection.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered transdermally.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by inhalation or by intranasal or transmucosaladministration.

Alternatively, a pharmaceutical composition of the present disclosurecan be administered by the intravaginal route.

A pharmaceutical composition of the present disclosure can contain fromabout 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percentby weight, of a Compound of the Disclosure, e.g., about 1%, about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,or about 75% by weight of a Compound of the Disclosure.

A pharmaceutical composition of the present disclosure is manufacturedin a manner which itself will be known in view of the instantdisclosure, for example, by means of conventional mixing, granulating,dragee-making, dissolving, extrusion, or lyophilizing processes. Thus,pharmaceutical compositions for oral use can be obtained by combiningthe active compound with solid excipients, optionally grinding theresulting mixture and processing the mixture of granules, after addingsuitable auxiliaries, if desired or necessary, to obtain tablets ordragee cores.

Suitable excipients include fillers such as saccharides (for example,lactose, sucrose, mannitol or sorbitol), cellulose preparations, calciumphosphates (for example, tricalcium phosphate or calcium hydrogenphosphate), as well as binders such as starch paste (using, for example,maize starch, wheat starch, rice starch, or potato starch), gelatin,tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, one ormore disintegrating agents can be added, such as the above-mentionedstarches and also carboxymethyl-starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodiumalginate.

Auxiliaries are typically flow-regulating agents and lubricants such as,for example, silica, talc, stearic acid or salts thereof (e.g.,magnesium stearate or calcium stearate), and polyethylene glycol. Drageecores are provided with suitable coatings that are resistant to gastricjuices. For this purpose, concentrated saccharide solutions can be used,which may optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate can be used. Dye stuffs orpigments can be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Examples of other pharmaceutical preparations that can be used orallyinclude push-fit capsules made of gelatin, or soft, sealed capsules madeof gelatin and a plasticizer such as glycerol or sorbitol. The push-fitcapsules can contain a compound in the form of granules, which can bemixed with fillers such as lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers, or in the form of extruded multiparticulates. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as fatty oils or liquid paraffin. In addition,stabilizers can be added.

Possible pharmaceutical preparations for rectal administration include,for example, suppositories, which consist of a combination of one ormore active compounds with a suppository base. Suitable suppositorybases include natural and synthetic triglycerides, and paraffinhydrocarbons, among others. It is also possible to use gelatin rectalcapsules consisting of a combination of active compound with a basematerial such as, for example, a liquid triglyceride, polyethyleneglycol, or paraffin hydrocarbon.

Suitable formulations for parenteral administration include aqueoussolutions of the active compound in a water-soluble form such as, forexample, a water-soluble salt, alkaline solution, or acidic solution.Alternatively, a suspension of the active compound can be prepared as anoily suspension. Suitable lipophilic solvents or vehicles for such assuspension may include fatty oils (for example, sesame oil), syntheticfatty acid esters (for example, ethyl oleate), triglycerides, or apolyethylene glycol such as polyethylene glycol-400 (PEG-400). Anaqueous suspension may contain one or more substances to increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran. The suspension mayoptionally contain stabilizers.

In another embodiment, the present disclosure provides kits whichcomprise a Compound of the Disclosure (or a composition comprising aCompound of the Disclosure) packaged in a manner that facilitates theiruse to practice methods of the present disclosure. In one embodiment,the kit includes a Compound of the Disclosure (or a compositioncomprising a Compound of the Disclosure) packaged in a container, suchas a sealed bottle or vessel, with a label affixed to the container orincluded in the kit that describes use of the compound or composition topractice the method of the disclosure. In one embodiment, the compoundor composition is packaged in a unit dosage form. The kit further caninclude a device suitable for administering the composition according tothe intended route of administration.

General Synthesis of Compounds

Compounds of the Disclosure are prepared using methods known to thoseskilled in the art in view of this disclosure, or by the illustrativemethods shown in the General Schemes below. In the General Schemes, R¹,R^(2a), R^(2b), R^(3b), R^(3b), R^(4a), R^(5a), and Z of Formulae A-Dare as defined in connection with Formula I, unless otherwise indicated.In any of the General Schemes, suitable protecting can be employed inthe synthesis, for example, when Z is (amino)alkyl or any other groupthat may group that may require protection, or when R⁸ is amino,(amino)alkyl, or any other group that may require protection. (See,Wuts, P. G. M.; Greene, T. W., “Greene's Protective Groups in OrganicSynthesis”, 4th Ed., J. Wiley & Sons, N Y, 2007).

Compound A is converted to compound B (i.e, a compound having Formula I,wherein R^(2b), R^(3b), R^(4b), R^(5b), and R⁶ are each hydrogen, and Xis —S(═O)₂—) by coupling with a suitable sulfonyl chloride (Z—SO₂Cl) inthe presence of a suitable base such as TEA or DIPEA in a suitablesolvent such as dichloromethane, acetonitrile, or DMF.

Compound A is converted to compound C (i.e, a compound having Formula I,wherein R^(2b), R^(3b), R^(4b), R^(5b), and R⁶ are each hydrogen, and Xis —C(═O)—) by coupling with a suitable acide chloride (Z—COCl) in thepresence of a suitable base such as TEA or DIPEA in a suitable solventsuch as dichloromethane, acetonitrile, or DMF, or by coupling with asuitable carboxylic acid (Z—CO₂H) in the presence of a suitable couplingreagent such as HATU and a suitable base such as TEA or DIPEA in asuitable solvent such as dichloromethane, acetonitrile, or DMF.

Compound A is converted to compound D (i.e, a compound having Formula I,wherein R^(2b), R^(3b), R^(4b), R^(5b), and R⁶ are each hydrogen, and Xis —C(═O)C(R⁸)(H)—) by coupling with a suitable carboxylic acid(Z—C(H)R⁸—CO₂H) in the presence of a suitable coupling reagent such asHATU and a suitable base such as TEA or DIPEA in a suitable solvent suchas dichloromethane, acetonitrile, or DMF.

EXAMPLES General Synthetic Methods

General methods and experimental procedures for preparing andcharacterizing compounds of Tables 1-3 are set forth in the generalschemes above and the examples below. Wherever needed, reactions wereheated using conventional hotplate apparatus or heating mantle ormicrowave irradiation equipment. Reactions were conducted with orwithout stirring, under atmospheric or elevated pressure in either openor closed vessels. Reaction progress was monitored using conventionaltechniques such as TLC, HPLC, UPLC, or LCMS using instrumentation andmethods described below. Reactions were quenched and crude compoundsisolated using conventional methods as described in the specificexamples provided. Solvent removal was carried out with or withoutheating, under atmospheric or reduced pressure, using either a rotary orcentrifugal evaporator.

Compound purification was carried out as needed using a variety oftraditional methods including, but not limited to, preparativechromatography under acidic, neutral, or basic conditions using eithernormal phase or reverse phase HPLC or flash columns or Prep-TLC plates.Compound purity and mass confirmations were conducted using standardHPLC and/or UPLC and/or MS spectrometers and/or LCMS and/or GC equipment(i.e., including, but not limited to the following instrumentation:Waters Alliance 2695 with 2996 PDA detector connected with ZQ detectorand ESI source; Shimadzu LDMS-2020; Waters Acquity H Class with PDAdetector connected with SQ detector and ESI source; Agilent 1100 Serieswith PDA detector; Waters Alliance 2695 with 2998 PDA detector; AB SCIEXAPI 2000 with ESI source; Agilent 7890 GC). Exemplified compounds weredissolved in either MeOH or MeCN to a concentration of approximately 1mg/mL and analyzed by injection of 0.5-10 μL into an appropriate LCMSsystem using the methods provided in the following table. In each casethe flow rate is 1 mL/min. LCMS data are presented in Tables 1A, 2A, and3A.

MS MS Heat Detec- Mobile Mobile Block tor Phase Phase Gradient TempVoltage Method Column A B Profile (° C.) (kV) A Shim- Water/ ACN/ 5% to100% 250 1.5 pack 0.05% 0.05% B in 2.0 XR-ODS TFA TFA minutes, 2.2 μm100% B for 3.0 × 1.1 minutes, 50 mm 100% to 5% B in 0.2 minutes, thenstop B Gemini- Water/ ACN 5% to 100% 200 0.75 NX 3 μm 0.04% B in 2.0 C18110A Ammonia minutes, 100% B for 1.1 minutes, 100% to 5% B in 0.1minutes, then stop C Shim- Water/ ACN/ 5% to 100% 250 0.85 pack 0.05%0.05% B in 2.0 XR-ODS TFA TFA minutes, 1.6 μm 100% B for 2.0 × 1.1minutes, 50 mm 100% to 5% B in 0.1 minutes, then stop D Shim- Water/ACN/ 5% to 100% 250 0.95 pack 0.05% 0.05% B in 2.0 XR-ODS TFA TFAminutes, 2.2 μm 100% B for 3.0 × 1.1 minutes, 50 mm 100% to 5% B in 0.1minutes, then stop

Compound structure confirmations were carried out using standard 300 or400 MHz NMR spectrometers with nOe's conducted whenever necessary.

The following abbreviations are used herein:

Abbreviation Meaning ACN acetonitrile atm. atmosphere DCMdichloromethane DHP dihydropyran DIBAL diisobutyl aluminum hydride DIEAdiisopropyl ethylamine DMF dimethyl formamide DMF-DMA dimethyl formamidedimethyl acetal DMSO dimethyl sulfoxide Dppf1,1′-bis(diphenylphosphino)ferrocene EA ethyl acetate ESI electrosprayionization EtOH Ethanol FA formic acid GC gas chromatography H hour Hexhexanes HMDS hexamethyl disilazide HPLC high performance liquidchromatography IPA Isopropanol LCMS liquid chromatography/massspectrometry MeOH Methanol Min Minutes NBS N-bromo succinimide NCSN-chloro succinimide NIS N-iodo succinimide NMR nuclear magneticresonance nOe nuclear Overhauser effect Prep. Preparative PTSApara-toluene sulfonic acid Rf retardation factor rt room temperature RTretention time sat. Saturated SGC silica gel chromatography TBAFtetrabutyl ammonium fluoride TEA Triethylamine TFA trifluoroacetic acidTHF Tetrahydrofuran TLC thin layer chromatography UPLC ultra performanceliquid chromatography

Example 1 Synthesis of 5-cyclopropylisoxazole-3-carboxylic acid

Step 1: Synthesis of ethyl 4-cyclopropyl-2,4-dioxobutanoate

Into a 10-L 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen Na (164 g, 1.20 equiv) was added inportions to ethanol (5 L). A solution of (CO₂Et)₂ (869 g, 1.00 equiv)and 1-cyclopropylethan-1-one (500 g, 5.94 mol, 1.00 equiv) was addeddropwise with stirring at 0-20° C. The resulting solution was stirredfor 1 h at 20-30° C. and then for an additional 1 h at 80° C. Theresulting solution was diluted with 15 L of H₂O. The pH was adjusted to2 with hydrochloric acid (12N). The resulting solution was extractedwith ethyl acetate and the organic layers combined and washed withNaHCO₃ (sat. aq.). The extract was concentrated under vacuum yielding820 g (crude) of ethyl 4-cyclopropyl-2,4-dioxobutanoate as yellow oil.TLC (ethyl acetate/petroleum ether=1/5): Rf=0.5.

Step 2: Synthesis of ethyl 5-cyclopropylisoxazole-3-carboxylate

Into a 10 L round-bottom flask, was placed a solution of ethyl4-cyclopropyl-2,4-dioxobutanoate (177 g) in ethanol (1.1 L) andNH₂OH—HCl (200 g). The resulting solution was stirred for 1 h at 20-30°C. The resulting solution was allowed to react, with stirring, for anadditional 1 h at 80° C. The resulting mixture was concentrated undervacuum. The residue was purified on a silica gel column with ethylacetate/petroleum ether (1/10). This resulted in 143 g (the two stepyield was 66.3%) of ethyl 5-cyclopropylisoxazole-3-carboxylate as ayellow oil. TLC (ethyl acetate/petroleum ether=1/5): Rf=0.2.

Step 3: Synthesis of 5-cyclopropylisoxazole-3-carboxylic acid

Into a 10-L round-bottom flask was placed ethyl5-cyclopropylisoxazole-3-carboxylate (280 g, 1.55 mol, 1.00 equiv) and asolution of sodium hydroxide (74.3 g, 1.20 equiv) in water (4 L). Theresulting solution was stirred for 1 h at room temperature. Theresulting mixture was washed with ether. The pH value of the aqueoussolution was adjusted to 2-3 with hydrochloric acid (12N). The resultingsolution was extracted with ethyl acetate and the organic layerscombined and concentrated under vacuum. This resulted in 220 g (93%) of5-cyclopropylisoxazole-3-carboxylic acid as an off-white solid. LCMS(method A, ESI): RT=1.99 min, m/z=153.9 [M+H]⁺. ¹H-NMR (300 MHz CDCl₃):8.42 (brs, 1H), 6.37 (s, 1H), 2.16-2.05 (m, 1H), 1.29-1.12 (m, 2H),1.12-0.99 (m, 2H) ppm.

Example 2 Synthesis of5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride and5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Step 1: Synthesis of (2S)-tert-butyl4-amino-2-methylpiperidine-1-carboxylate

Into a 10-L round-bottom flask was placed methanol (5 L), HCOONH₄ (190g, 3.01 mol, 37.80 equiv), acetic acid (5 g, 83.26 mmol, 1.04 equiv) andtert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (17 g, 79.71mmol, 1.00 equiv). Then NaBH₃CN (10 g, 159.13 mmol, 2.00 equiv) wasadded batchwise. The resulting solution was stirred at 25° C. overnight.The resulting mixture was concentrated under vacuum. The resultingsolution was diluted with 500 mL of ethyl acetate. The resultingsolution was washed with 3×500 mL of brine (sat.). This resulted in 15.5g (91%) of tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylate asoff-white oil. LCMS (method A, ESI): RT=1.21 min, m/z=215.1 [M+H]⁺.

Step 2: Synthesis of (2S)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

Into a 1 L round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed dichloromethane (500 mL), HOBT (15 g,111.01 mmol, 1.53 equiv), EDCI (20 g, 104.33 mmol, 1.44 equiv),5-cyclopropyl-1,2-oxazole-3-carboxylic acid (13.3 g, 86.85 mmol, 1.20equiv) and tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylate(15.5 g, 72.33 mmol, 1.00 equiv). Then triethylamine (36 g, 355.77 mmol,4.92 equiv) was added dropwise. The resulting solution was stirred for 2hours at 25° C. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 500 mL of ethyl acetate. Theresulting mixture was washed with 3×500 mL of water. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1:10). This resulted in 14 g (55%) of tert-butyl(2S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas light yellow oil. LCMS (method A, ESI): RT=2.05 min, m/z=350.2[M+H]⁺.

Step 3: Synthesis of tert-butyl(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateand tert-butyl(2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate

The crude product was purified by Chrial-HPLC with the followingconditions: Column name: CHIRALPAK AD-H, 4.6*150 mm, 5 um, Co-Solvent:EtOH (0.1% DEA), % Co-Solvent: Hexane, 25.000, Detector: 220 nm. Theresulting solution was concentrated under vacuum. This resulted in 9.8 g(70%) of tert-butyl(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas white solid. ¹H-NMR (400 MHz, DMSO): δ 8.54-8.52 (m, 1H), 6.47 (s,1H), 3.94-3.87 (m, 2H), 3.57-3.53 (m, 1H), 3.32-3.26 (m, 1H), 2.20-2.16(m, 1H), 1.80-1.63 (m, 4H), 1.39 (s, 9H), 1.16-1.15 (m, 3H), 1.10-1.06(m, 2H), 0.93-0.89 (m, 2H) ppm. And 3.3 g (24%) of tert-butyl(2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas a light yellow solid. ¹H-NMR (400 MHz, DMSO): δ 8.54-8.52 (m, 1H),6.46 (s, 1H), 4.54-4.30 (m, 1H), 4.28-4.04 (m, 1H), 4.00-3.68 (m, 1H),3.10-2.70 (m, 1H), 2.19-2.15 (m, 1H), 1.76-1.73 (m, 1H), 1.63-1.59 (m,2H), 1.39-1.35 (m, 10H), 1.13-1.08 (m, 5H), 1.00-0.82 (m, 2H) ppm.

Step 4: Synthesis of5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride and5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Into a 250-mL round-bottom flask was placed dichloromethane (100 mL),tert-butyl(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(9.8 g, 28.05 mmol, 1.00 equiv). To the above hydrogen chloride wasintroduced. The resulting solution was stirred for 2 hours at 25° C. Theresulting mixture was concentrated under vacuum. This resulted in 8.6 gof5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride as a white solid. ¹HNMR (400 MHz, MeOD): δ 6.40 (s, 1H),4.24-4.10 (m, 1H), 3.55-3.45 (m, 1H), 3.40-3.35 (m, 1H), 3.19-3.15 (m,1H), 2.24-2.15 (m, 3H), 1.82-1.77 (m, 1H), 1.63-1.60 (m, 1H), 1.93-1.37(m, 3H), 1.21-1.13 (m, 2H), 1.00-0.96 (m, 2H) ppm. LCMS (method A, ESI):RT=1.13 min, m/z=250.1 [M−HCl+H]⁺.

Into a 100-mL round-bottom flask was placed dichloromethane (50 mL),tert-butyl(2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(3.3 g, 9.44 mmol, 1.00 equiv). To the above hydrogen chloride wasintroduced. The resulting solution was stirred for 2 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 3 g (crude) of5-cyclopropyl-N-[(2S,4R)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride as a light yellow solid. ¹H NMR (400 MHz, MeOD): δ6.41 (s,1H), 4.36-4.34 (m, 1H), 3.62-3.59 (m, 1H), 3.40-3.35 (m, 2H), 2.21-2.03(m, 4H), 1.90-1.82 (m, 1H), 1.39-1.37 (m, 3H), 1.18-1.14 (m, 2H),1.00-0.96 (m, 2H) ppm. LCMS (method A, ESI): RT=1.03 min, m/z=250.1[M−HCl+H]⁺.

Example 3 Synthesis of5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride and5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Step 1: Synthesis of (2R)-tert-butyl4-amino-2-methylpiperidine-1-carboxylate

Into a 5000-mL round-bottom flask was placed tert-butyl(2R)-2-methyl-4-oxopiperidine-1-carboxylate (8.53 g, 40.00 mmol, 1.00equiv), HCOONH₄ (100.8 g, 1.60 mol, 39.97 equiv), methanol (4 L) andacetic acid (2.4 g, 39.97 mmol, 1.00 equiv). Then NaBH₃CN (5.04 g, 80.00mmol, 2.00 equiv) was added batchwise. The resulting solution wasstirred for 15 h at room temperature. The resulting mixture wasconcentrated under vacuum. The resulting solution was diluted with 200mL of brine (sat.). The resulting solution was extracted with 3×100 mLof ethyl acetate and the organic layers combined. The resulting mixturewas washed with 3×100 mL of brine and concentrated under vacuum. Thisresulted in 10.5 g (98%) of tert-butyl(2R)-4-amino-2-methylpiperidine-1-carboxylate as a white solid. LCMS(method A, ESI): RT=1.06 min, m/z=159.0 [M−56+H]⁺. \

Step 2: Synthesis of (2R,4R)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylateand (2R,4S)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

Into a 500-mL round-bottom flask was placed5-cyclopropyl-1,2-oxazole-3-carboxylic acid (6.12 g, 39.96 mmol, 1.00equiv), tert-butyl (2R)-4-amino-2-methylpiperidine-1-carboxylate (8.57g, 39.99 mmol, 1.00 equiv), dichloromethane (300 g), TEA (12.12 g,120.00 mmol, 3.00 equiv) and HATU (22.8 g, 60.00 mmol, 1.50 equiv). Theresulting solution was stirred for 15 h at room temperature. Theresulting mixture was then washed with 2×100 mL of Na₂CO₃ (1M, aq.).Then the organic phase was dried over Na₂SO₄ and concentrated undervacuum. The residue was purified by column chromatography (C18 gel,CH₃CN/H₂O=1:1) to give 10.8 g diastereomeric tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate.Then the purified product was separated by Prep-SFC with the followingconditions (prep SFC 350): Column, CHIRALPAK AD-H SFC, 5×25 cm, 5 um;mobile phase, CO₂(50%), methanol (50%); Detector, uv 220 nm. This wasresulted in 7.48 g (54%) of tert-butyl(2R,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas light yellow oil. ¹H-NMR (300 MHz, CDCl₃): 6.86 (d, J=6.9 Hz, 1H),6.33 (s, 1H), 4.30-4.15 (m, 2H), 3.93-3.80 (m, 1H), 3.22-3.07 (m, 1H),2.20-1.90 (m, 3H), 1.79-1.65 (m, 2H), 1.46 (s, 9H), 1.26 (d, J=6.9 Hz,3H), 1.17-1.06 (m, 2H), 1.06-0.94 (m, 2H) ppm. LCMS (method A, ESI):RT=1.46 min, m/z=372.2 [M+H]⁺. And 2.52 g (18%) of tert-butyl(2R,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas a light yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ 6.55 (d, J=8.1 Hz,1H), 6.33 (s, 1H), 4.63-4.39 (m, 1H), 4.39-4.15 (m, 1H), 4.15-3.95 (m,1H), 3.0-2.85 (m, 1H), 2.15-1.98 (m, 2H), 1.92-1.78 (m, 1H), 1.65-1.50(m, 1H), 1.46 (s, 9H), 1.42-1.26 (m, 1H), 1.23 (d, J=6.9 Hz, 3H),1.17-1.06 (m, 2H), 1.06-0.94 (m, 2H) ppm. LCMS (method A, ESI): RT=1.46min, m/z=372.2 [M+H]⁺.

Step 3: Synthesis of5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Into a 250-mL round-bottom flask was placed tert-butyl(2R,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(7.48 g, 21.41 mmol, 1.00 equiv) and 1,4-dioxane (50 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredfor 15 h at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 6.03 g (99%) of5-cyclopropyl-N-[(2R,4R)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride as a white solid. LCMS (method D, ESI): RT=0.58 min,m/z=250.0 [M+H]⁺.

Step 4: Synthesis of5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Into a 100-mL round-bottom flask was placed tert-butyl(2R,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(2.52 g, 7.21 mmol, 1.00 equiv) and 1,4-dioxane (15 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredfor 15 h at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 2.0 g (97%) of5-cyclopropyl-N-[(2R,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride as a light yellow solid. LCMS (method A, ESI): RT=1.12min, m/z=250.0 [M+H]⁺.

Example 4 Synthesis ofN-((2S,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride salt

Step 1: Synthesis of tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate

Into a 5-L round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl2-benzyl-4-oxopiperidine-1-carboxylate (5 g, 17.28 mmol, 1.00 equiv),methanol (4 L), acetic acid (2.076 g, 34.57 mmol, 2.00 equiv) andHCOONH₄ (43.599 g). The resulting solution was stirred for 0.5 h at roomtemperature. Then NaBH₃CN (2.180 g, 34.69 mmol, 2.01 equiv) was added bybatchwise. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 200 mL of EA. The resulting mixturewas washed with 4×100 mL of brine (sat.). The organic phase wascollected and concentrated under vacuum. The solid was dried in an ovenunder reduced pressure. This resulted in 5 g (100%) of tert-butyl4-amino-2-benzylpiperidine-1-carboxylate as light yellow oil. LCMS(method C, ESI): RT=0.89 min, m/z=235.0 [M−56+H]⁺.

Step 2: Synthesis of (2R,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate

(2S,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate

(2S,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate

and

(2R,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl4-amino-2-benzylpiperidine-1-carboxylate (5 g, 17.22 mmol, 1.00 equiv),dichloromethane (100 mL), TEA (8.707 g, 86.05 mmol, 5.00 equiv),5-cyclopropyl-1,2-oxazole-3-carboxylic acid (3.957 g, 25.84 mmol, 1.50equiv), HATU (19.655 g, 51.69 mmol, 3.00 equiv). The resulting solutionwas stirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum. The resulting solution was diluted with 200mL of EA. The resulting mixture was washed with 3×200 mL of brine(sat.). The organic phase was collected and dried over anhydrous sodiumsulfate and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:10). Thecollected fractions were combined and concentrated under vacuum. Thecrude product 2.9 g was purified by Prep-SFC with the followingconditions (prep SFC 350-2): Column, Chiralpak AD-H, 5×25 cm, Sum;mobile phase, CO₂(70%), IPA (30%) and DCM/MeOH=1/3:100; Detector, uv 210nm yielding two fractions: first peak—cis enantiomers 1.7 g, second peaktrans enantiomers 0.6 g.

These products were further purified by SFC. The cis mixtures werepurified by Prep-SFC with the following conditions (prep SFC 350-2):Column, Chiralpak AS-H, 5*25 cm, Sum; mobile phase, CO₂ (70%), IPA (30%)and MeOH (50%); Detector, uv 210 nm. This resulted in 820 mg of(2R,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylateas yellow oil and 870 mg of (2S,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylateas yellow oil. (2R,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate:¹H-NMR (300 MHz, CD₃Cl) δ: 7.26-7.17 (m, 5H), 6.88 (d, J=6.9 Hz, 1H),6.32 (d, J=0.6 Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m, 1H), 2.12-1.98 (m, 2H),1.91-1.66 (m, 3H), 1.37 (d, J=2.7 Hz, 9H), 1.18-1.09 (m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT=1.59 min, m/z=326.0 [M-Boc+H]⁺.(2S,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate:¹H-NMR (300 MHz, CD₃Cl) δ: 7.26-7.17 (m, 5H), 6.88 (d, J=6.9 Hz, 1H),6.32 (d, J=0.6 Hz, 1H), 4.38-4.28 (m, 1H), 4.27-4.16 (m, 1H), 4.09-3.98(m, 1H), 3.18-2.99 (m, 2H), 2.82-2.75 (m, 1H), 2.12-1.98 (m, 2H),1.91-1.66 (m, 3H), 1.37 (d, J=2.7 Hz, 9H), 1.18-1.09 (m, 2H), 1.02-0.92(m, 2H) ppm. LCMS (method A, ESI): RT=1.59 min, m/z=326.0 [M-Boc+H]⁺.

The trans mixture was purified by Prep-SFC with the following conditions(prep SFC 350): Column, Phenomenex Lux 5u Cellulose-4250*50mm00G-4491-V0-AX664184-1; mobile phase, CO₂(50%) and MeOH (50%),Detector, uv 220 nm. This resulted in 250 mg of (2S,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylateas yellow oil and 260 mg of (2R,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylateas yellow oil. (2S,4R)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate:¹H-NMR (300 MHz, CD₃Cl) δ: 7.26-7.17 (m, 5H), 6.88 (d, J=6.9 Hz, 1H),6.32 (s, 1H), 4.81-3.91 (m, 3H), 3.08 (t, J=13.5 Hz, 1H), 2.96-2.81 (m,2H), 2.11-2.02 (m, 2H), 1.95 (d, J=10.5 Hz, 1H), 1.52-1.22 (m, 11H),1.15-1.05 (m, 2H), 1.02-0.92 (m, 2H) ppm. LCMS (method A, ESI): RT=1.58min, m/z=448.0 [M+Na]⁺. (2R,4S)-tert-butyl2-benzyl-4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate:¹H-NMR (300 MHz, CD₃Cl) δ: 7.26-7.17 (m, 5H), 6.88 (d, J=6.9 Hz, 1H),6.32 (s, 1H), 4.81-3.91 (m, 3H), 3.08 (t, J=13.5 Hz, 1H), 2.96-2.81 (m,2H), 2.11-2.02 (m, 2H), 1.95 (d, J=10.5 Hz, 1H), 1.52-1.22 (m, 11H),1.15-1.05 (m, 2H), 1.02-0.92 (m, 2H) ppm. LCMS (method A, ESI): RT=1.58min, m/z=448.0 [M+Na]⁺.

Step 3: Synthesis ofN-((2R,4R)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

N-((2S,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

N-((2S,4R)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

and

N-((2R,4S)-2-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl(2R,4R)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidine-1-carboxylate(820 mg, 1.93 mmol, 1.00 equiv) and 1,4-dioxane (20 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 670 mg (96%) ofN-[(2R,4R)-2-benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. LCMS (method A, ESI): RT=1.11 min,m/z=326.0 [M+H]⁺.

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidine-1-carboxylate(870 mg, 2.05 mmol, 1.00 equiv) and 1,4-dioxane (20 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 710 mg (96%) ofN-[(2S,4S)-2-benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. LCMS (method A, ESI): RT=1.10 min,m/z=326.0 [M+H]⁺.

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl(2S,4R)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidine-1-carboxylate(250 mg, 0.59 mmol, 1.00 equiv) and 1,4-dioxane (10 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 190 mg (91%) ofN-[(2S,4R)-2-benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. LCMS (method A, ESI): RT=1.11 min,m/z=326.0 [M+H]⁺.

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed tert-butyl(2R,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidine-1-carboxylate(260 mg, 0.61 mmol, 1.00 equiv) and 1,4-dioxane (10 mL). Then hydrogenchloride was introduced into mixture. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. This resulted in 200 mg (91%) ofN-[(2R,4S)-2-benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. LCMS (method A, ESI): RT=1.11 min,m/z=326.0 [M+H]⁺.

Example 5 Synthesis ofN-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

and

N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Step 1: Synthesis of (1R,5S,E)-tert-butyl3-(hydroxyimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate

Into a 2000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of (1R,5S)-tert-butyl3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate (25 g, 104.03 mmol, 1.00equiv) in ethanol (500 mL) at room temperature. This was followed by theaddition of hydroxylamine hydrochloride (14.5 g, 208.66 mmol, 2.01equiv) at room temperature. To this was added a solution of sodiumhydroxide (8.4 g, 210.00 mmol, 2.02 equiv) in water (250 mL) by dropwisewith stirring at room temperature. The resulting solution was stirredfor 8 h at 95° C. The resulting mixture was concentrated under vacuum.The resulting solution was diluted with 250 mL of H₂O. The resultingsolution was extracted with 3×250 mL of dichloromethane and the organiclayers combined. The resulting solution was concentrated under vacuum.This resulted in 26 g (98%) of (1R,5S,E)-tert-butyl3-(hydroxyimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate as a whitesolid. ¹H NMR (300 MHz, DMSO) δ: 10.40 (s, 1H), 4.29 (s, 2H), 3.04 (d,1H), 2.44-2.27 (m, 2H), 1.99 (d, 1H), 1.79-1.58 (m, 5H), 1.49-1.45 (m,1H), 1.41 (s, 9H) ppm. LCMS (Method D, ESI): RT=1.76 min, m/z=240.0[M−15+H]⁺.

Step 2: Synthesis of (1R,3s,5S)-tert-butyl3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate and(1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate

Into a 5000-mL round-bottom flask was placed a solution of(1R,5S,E)-tert-butyl3-(hydroxyimino)-9-azabicyclo[3.3.1]nonane-9-carboxylate (26 g, 101.83mmol, 1.00 equiv) in methanol (4500 mL) at room temperature. This wasfollowed by the addition of Raney-Ni (13 g) at room temperature. Theflask was evacuated and flushed three times with nitrogen, then followedby flushing with hydrogen. The mixture was stirred 7 h at roomtemperature under an atmosphere of hydrogen (maintained with 2 atmpressure). The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 21.2 g (86%) of(1R,3s,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylateand (1R,3r,5S)-tert-butyl3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate as a white solid. ¹H NMR(400 MHz, CDCl₃) δ: 4.55-4.21 (m, 2H), 3.66-3.58 (m, 0.27H), 2.73-2.62(m, 0.73H), 2.31-2.18 (m, 1H), 2.01-1.89 (m, 1H), 1.89-1.75 (m, 3H),1.70-1.52 (m, 3H), 1.52-1.49 (m, 1H), 1.46 (s, 9H), 1.45-1.35 (m, 1.5H),1.21-1.09 (m, 1.5H) ppm. LCMS (Method D, ESI): RT=1.28 min, m/z=282.0[M+H+CH₃CN]⁺.

Step 3: Synthesis of (1R,3s,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateand (1R,3r,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate

Into a 1000-mL round-bottom flask was placed (1R,3s,5S)-tert-butyl3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate and(1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate(20.5 g, 84.94 mmol, 1.00 equiv), dichloromethane (410 mL),5-cyclopropyl-1,2-oxazole-3-carboxylic acid (19.6 g, 127.99 mmol, 1.51equiv), EDCI (32.6 g, 170.06 mmol, 2.00 equiv), HOBT (17.3 g, 128.03mmol, 1.51 equiv), TEA (43.1 g, 425.93 mmol, 5.01 equiv). The resultingsolution was stirred for 3 h at room temperature. The resulting solutionwas diluted with 400 mL of DCM. The resulting mixture was washed with2×400 mL of H₂O. The residue was purified on a silica gel column withdichloromethane/methanol (20:1). This resulted in 30.3 g (95%) of(1R,3s,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateand (1R,3r,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 6.40 (d, 1H), 5.01-4.90 (m,0.33H), 4.55-4.29 (m, 2H), 3.92-3.78 (m, 0.67H), 2.37-2.21 (m, 1.4H),2.21-1.99 (m, 2.6H), 1.95-1.70 (m, 2H), 1.68-1.54 (m, 5H), 1.50 (s, 9H),1.20-1.10 (m, 2H), 1.01-0.91 (m, 2H) ppm. LCMS (Method D, ESI): RT=2.22min, m/z=361.0 [M-15+H]⁺.

Step 4: Synthesis of (1R,3s,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateand (1R,3r,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate

The mixture of diastereomers (30 g) was purified by prep-SFC with thefollowing conditions: Column: Phenomenex Lux 5u Cellulose-35*25 cm,5umChiral-P(Lux-3)001608862-1; Detector: UV 220 nm; Mobile Phase:CO₂(70%), MeOH (30%). The resulting solution was concentrated undervacuum. This resulted in 20.6 g (95%) of (1R,3r,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 6.35 (s, 1H), 4.47 (d, 2H),3.90-3.75 (m, 1H), 2.35-2.23 (m, 2H), 2.21-2.02 (m, 2H), 1.69-1.52 (m,7H), 1.50 (s, 9H), 1.18-1.10 (m, 2H), 0.98-0.90 (m, 2H) ppm. LCMS(Method D, ESI): RT=2.20 min, m/z=320.0 [M-56+H]⁺. And 8.0 g (86%) of(1R,3s,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylateas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 6.36 (s, 1H), 5.02-4.91 (m,1H), 4.34 (s, 2H), 2.22-2.10 (m, 1H), 2.09-1.97 (m, 3H), 1.93-1.64 (m,7H), 1.48 (s, 9H), 1.18-1.10 (m, 2H), 0.98-0.90 (m, 2H) ppm. LCMS(Method D, ESI): RT=2.19 min, m/z=320.0 [M-56+H]⁺.

Step 5: Synthesis ofN-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 250-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate(20.6 g, 54.72 mmol, 1.00 equiv) and dichloromethane (150 mL). To theabove hydrogen chloride was introduced. The resulting solution wasstirred for 2 h at room temperature. The resulting solution was dilutedwith 400 mL of H₂O. The pH value of the solution was adjusted to 9 withpotassium carbonate. The resulting solution was extracted with 3×250 mLof dichloromethane and the organic layers combined and concentratedunder vacuum. This resulted in 14.2 g (94%) ofN-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 6.38 (s, 1H), 4.29-4.20 (m,1H), 3.36 (d, 2H), 2.28-2.11 (m, 3H), 2.10-2.00 (m, 1H), 1.79-1.69 (m,2H), 1.58-1.37 (m, 5H), 1.19-1.11 (m, 2H), 0.98-0.92 (m, 2H) ppm. LCMS(Method D, ESI): RT=1.23 min, m/z=317.0 [M+H+CH₃CN]⁺.

Step 6: Synthesis ofN-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 250-mL round-bottom flask was placed (1R,3s,5S)-tert-butyl3-(5-cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate(8.0 g, 21.25 mmol, 1.00 equiv), dichloromethane (100 mL). To the abovehydrogen chloride was introduced. The resulting solution was stirred for2 h at room temperature. The resulting solution was diluted with 300 mLof H₂O. The pH value of the solution was adjusted to 9 with potassiumcarbonate. The resulting solution was extracted with 3×100 mL ofdichloromethane and the organic layers combined and concentrated undervacuum. This resulted in 5.5 g (94%) ofN-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 6.38 (s, 1H), 4.89-4.80 (m,1H), 3.22 (s, 2H), 2.21-2.13 (m, 1H), 2.09-1.88 (m, 5H), 1.85-1.70 (m,5H), 1.19-1.11 (m, 2H), 0.98-0.92 (m, 2H) ppm. LCMS (Method D, ESI):RT=1.20 min, m/z=276.0 [M+H]⁺.

Example 6 Synthesis ofN-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

and

N-((1R,3s,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Step 1: Synthesis of tert-butyl3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 2000-mL 3-necked round-bottom flask was placed HCOONH₄ (42 g,666.03 mmol, 30.00 equiv), acetic acid (1.3 g, 21.65 mmol, 1.00 equiv)and methanol (1.5 L). Then NaBH₃CN (2.8 g, 44.56 mmol, 2.00 equiv) wasadded into batch wise. This was followed by the addition of a solutionof tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (5 g, 22.19mmol, 1.00 equiv) in methanol (100 mL) dropwise with stirring at 25° C.The resulting solution was stirred for 12 h at 25° C. The resultingmixture was concentrated under vacuum. The resulting solution wasdiluted with 200 mL of H₂O. The resulting solution was extracted with3×200 mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 1×200 mL of brine (sat.). The mixture was driedover anhydrous sodium sulfate. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (9:1). This resulted in 4.8 g (90%)of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate ascolorless oil. LCMS (method D, ESI): RT=0.97 min, m/z=227.0 [M+H]⁺.

Step 2: Synthesis of tert-butyl(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylateand tert-butyl(1R,3s,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 250-mL round-bottom flask was placed tert-butyl3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (4 g, 17.67 mmol, 1.00equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid (2.7 g, 17.63 mmol,1.00 equiv), HATU (10 g, 26.30 mmol, 1.50 equiv), DIEA (5.7 g, 44.10mmol, 2.50 equiv), DMF (100 mL). The resulting solution was stirred for12 h at 25° C. The reaction was then quenched by the addition of 100 mLof water. The resulting solution was extracted with 3×100 mL of ethylacetate and the organic layers combined. The resulting mixture waswashed with 1×100 mL of brine. The mixture was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedon a silica gel column with ethyl acetate/petroleum ether (1:4). Theproduct (4.0 g) was further purified by Prep-SFC with the followingconditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-3, 5*25cm, Sum; mobile phase, CO₂(80%), methanol (20%); Detector, UV220 nm.This resulted in 800 mg (13%) of tert-butyl(1R,3s,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 6.53 (d, J=8.0 Hz, 1H),6.33 (s, 1H), 4.41-4.58 (m, 1H), 4.24-4.32 (m, 2H), 1.95-2.11 (m, 5H),1.80-1.84 (m, 2H), 1.57-1.63 (m, 2H), 1.50 (s, 9H), 1.16-1.28 (m, 2H),0.95-1.06 (m, 2H) ppm. LCMS (method D, ESI): RT=2.33 min, m/z=362.0[M+H]⁺ and 1.4 g (22%) of tert-butyl(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylateas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ: 7.21-7.23 (d, J=7.6 Hz,1H), 6.34 (s, 1H), 4.27-4.33 (m, 3H), 2.25-2.31 (m, 2H), 2.07-2.14 (m,3H), 1.91-1.95 (m, 2H), 1.76-1.80 (m, 2H), 1.49 (s, 9H), 1.16-1.28 (m,2H), 0.95-1.06 (m, 2H) ppm. LCMS (method D, ESI): RT=2.43 min, m/z=362.0[M+H]⁺.

Step 3: Synthesis ofN-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride andN-((1R,3s,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Into two 50-mL round-bottom flasks was separately placed tert-butyl(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate(600 mg, 1.66 mmol, 1.00 equiv) and tert-butyl(1R,3s,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate(600 mg, 1.66 mmol, 1.00 equiv). This was followed by the addition of 10mL of 1,4-dioxane into each flask. Then hydrogen chloride was introducedinto the two mixtures. The resulting solutions were stirred for 2 h at25° C. The resulting mixtures were concentrated under vacuum. Thisresulted in 480 mg (97%) ofN-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride LCMS (method D, ESI): RT=0.97 min, m/z=262.0 [M+H]⁺ and480 mg (97%) ofN-((1R,3s,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride as a light yellow solid. LCMS (method D, ESI): RT=0.95min, m/z=262.0 [M+H]⁺.

Example 7 Synthesis ofN-[1-[(2S)-3-amino-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride salt (Cpd. No. 121)

Step 1: Synthesis of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate

Into a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed 4-hydroxybenzaldehyde (6 g, 49.13mmol, 1.00 equiv) and ethanol (200 mL). Then ethyl 2-cyanoacetate (6.7g, 59.23 mmol, 1.21 equiv) and piperidine (2 mL) was added. Theresulting solution was stirred overnight at 90° C. The resulting mixturewas concentrated under vacuum. The residue was purified on a silica gelcolumn with ethyl acetate/petroleum ether (1:2). This resulted in 8.5 g(80%) of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate as a yellowsolid. ¹H-NMR (300 MHz, CDCl₃): δ 8.19 (s, 1H), 7.97 (d, J=8.7 Hz, 2H),6.99 (d, J=8.7 Hz, 2H), 6.11 (brs, 1H), 4.41-4.31 (m, 2H), 1.40 (t,J=7.2 Hz, 3H) ppm. LCMS (method A, ESI): RT=1.34 min, m/z=217.9 [M+H]⁺.

Step 2: Synthesis of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxyphenyl)methyl] propanoate

Into a 500-mL round-bottom flask was placed ethyl(2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate (8.5 g, 39.13 mmol, 1.00equiv), methanol (200 mL) and di-tert-butyl dicarbonate (9.4 g, 43.07mmol, 1.10 equiv). Then Raney-Ni (3 g) was added batchwise. Then H₂ wasintroduced into mixture and maintained at 2 atm pressure. The resultingsolution was stirred overnight at room temperature. The solids werefiltered out. The resulting mixture was concentrated under vacuum. Theresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:3). This resulted in 12 g (95%) of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxyphenyl)methyl]propanoateas a light yellow solid. LCMS (method C, ESI): RT=0.95 min, m/z=324.2[M+H]⁺.

Step 3: Synthesis of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3-iodophenyl)methyl]propanoate

Into a 250-mL round-bottom flask was placed ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxyphenyl)methyl]propanoate(5 g, 15.46 mmol, 1.00 equiv), TsOH (266 mg, 1.54 mmol, 0.10 equiv) anddichloromethane (80 mL). Then NIS (3.48 g, 15.47 mmol, 1.00 equiv) wasadded into at room temperature. The resulting solution was stirredovernight at room temperature. The resulting mixture was concentratedunder vacuum. The residue was purified on a silica gel column with ethylacetate/petroleum ether (1:3). This resulted in 4.2 g (60%) of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3-iodophenyl)methyl]propanoateas a light yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.46 (d, J=2.1 Hz,1H), 7.06-7.02 (m, 1H), 6.89 (d, J=9.6 Hz, 1H), 4.15-4.07 (m, 2H),3.32-3.24 (m, 2H), 2.84-2.72 (m, 3H), 1.43 (s, 9H), 1.19 (t, J=6.9 Hz,3H) ppm. LCMS (method A, ESI): RT=1.70 min, m/z=349.9 [M-Boc+H]⁺.

Step 4: Synthesis of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(prop-1-en-2-yl)phenyl]methyl]propanoate

Into a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3-iodophenyl)methyl]propanoate(4 g, 8.90 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.8 g, 10.71mmol, 1.20 equiv), Pd(dppf)Cl₂ (650 mg), Cs₂CO₃ (8.7 g, 26.62 mmol, 2.99equiv), and N,N-dimethylformamide (50 mL). The resulting solution wasstirred overnight at 100° C. The resulting solution was diluted with 40mL of NH₄Cl (sat. aq.). The resulting solution was extracted with 4×40mL of ethyl acetate and the organic layers combined. The resultingmixture was washed with 4×50 mL of NH₄Cl (sat. aq.). The resultingmixture was concentrated under vacuum. The residue was purified on asilica gel column with ethyl acetate/petroleum ether (1:5). Thisresulted in 1 g (31%) of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(prop-1-en-2-yl)phenyl]methyl]propanoateas light brown oil. LCMS (method A, ESI): RT=1.74 min, m/z=264.0[M-Boc+H]⁺.

Step 5: Synthesis of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-yl)phenyl]methyl]propanoate

Into a 250-mL round-bottom flask, was placed ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(prop-1-en-2-yl)phenyl]methyl]propanoate(1.3 g, 3.58 mmol, 1.00 equiv), ethyl acetate (40 mL) and 10% Palladiumcarbon (0.7 g). Then H₂ was introduced into mixture and maintained at 2atm pressure. The resulting solution was stirred overnight at roomtemperature. The solids were filtered out. The resulting mixture wasconcentrated under vacuum. This resulted in 1.0 g (76%) of ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoateas light yellow oil. LCMS (method D, ESI): RT=1.57 min, m/z=366.0[M+H]⁺.

Step 6: Synthesis of3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoicacid

Into a 250-mL round-bottom flask was placed ethyl3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoate(1 g, 2.74 mmol, 1.00 equiv), ethanol (40 mL), water (0.5 mL), sodiumhydroxide (0.45 g). The resulting solution was stirred for 6 h at roomtemperature. The resulting mixture was concentrated under vacuum. The pHvalue of the solution was adjusted to 4 with hydrochloric acid (12N).The resulting solution was extracted with 5×30 mL of ethyl acetate andthe organic layers combined and concentrated under vacuum. This resultedin 0.6 g (65%) of3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoicacid as colorless oil. LCMS (method A, ESI): RT=1.56 min, m/z=360.1[M+Na]⁺.

Step 7: Synthesis of tert-butylN-[3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamate

Into a 250-mL round-bottom flask was placed3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoicacid (600 mg, 1.78 mmol, 1.00 equiv),5-cyclopropyl-N-(piperidin-4-yl)-1,2-oxazole-3-carboxamide hydrochloride(750 mg, 2.76 mmol, 1.55 equiv), EDCI (0.85 g), HOBT (0.6 g) anddichloromethane (60 mL). Then TEA (0.9 g) was added into dropwise at 0°C. The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether(1:10). The product was further purified by Prep-HPLC with the followingconditions (2#-Waters 2767-2(HPLC-08)): Column, Xbridge Prep Phenyl, 5um, 19×150 mm; mobile phase, Water with 50 mmol ammonium bicarbonate andacetonitrile (10.0% acetonitrile up to 33.0% in 2 min, up to 53.0% in 8min, up to 100.0% in 1 min, down to 10.0% in 1 min); Detector, UV 254nm. This resulted in 650 mg (66%) of tert-butylN-[3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamateas a white solid. LCMS (method A, ESI): RT=1.69 min, m/z=455.2[M-Boc+H]⁺.

Step 8: Synthesis of tert-butylN-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamate

The tert-butylN-[3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamate(600 mg, 1.08 mmol, 1.00 equiv) was separated by Chiral-HPLC withfollowing conditions: (Chiral-p(Lux-4)003667995-2): Column, PhenomenexLux 5u Cellulose-4, AXIA Packed250*21.2 mm, 5 um, mobile phase, Phase A:Hex-HPLC and Phase B: EtOH-HPLC Gradient; Detector, uv 254/220 nm. Thisresulted in 256 mg (43%) of tert-butylN-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamateas a white solid. LCMS (method A, ESI): RT=1.68 min, m/z=455.3[M-Boc+H]⁺.

Step 9: Synthesis ofN-[1-[(2S)-3-Amino-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride salt

Into a 100-mL round-bottom flask was placed tert-butylN-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3-oxopropyl]carbamate(256 mg, 0.46 mmol, 1.00 equiv) and dichloromethane (20 mL). Thenhydrogen chloride was introduced into mixture. The resulting solutionwas stirred for 4 h at room temperature. The solids were collected byfiltration. The resulting filtrate was concentrated under vacuum. Thisresulted in 152.2 mg (67%) ofN-[1-[(2S)-3-amino-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. ¹H-NMR (300 MHz, CD₃OD): δ 6.99 (dd,J=20.4 and 2.1 Hz, 1H), 6.86-6.81 (m, 1H), 6.73-6.69 (m, 1H), 6.36 (d,J=0.6 Hz, 1H), 4.60-4.37 (m, 1H), 4.05-3.88 (m, 1H), 3.87-3.63 (m, 1H),3.50-3.36 (m, 1H), 3.30-2.98 (m, 3.5H), 2.88-2.72 (m, 3H), 2.62-2.45 (m,0.5H), 2.21-2.11 (m, 1H), 1.96-1.62 (m, 2H), 1.62-1.42 (m, 1H),1.40-1.24 (m, 0.5H), 1.23-1.18 (m, 6H), 1.18-1.09 (m, 2H), 1.02-0.90 (m,2H), 0.78-0.60 (m, 0.5H) ppm. LCMS (method D, ESI): RT=1.96 min,m/z=455.1 [M+H]⁺. ee=100%.

Example 8 Synthesis ofN-((2R,4S,5R)-1-((1r,4R)-4-aminocyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 420)

Step 1: Synthesis of tert-butyl 2,5-dimethylpyridin-4-ylcarbamate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of2,5-dimethylpyridin-4-amine (488 mg, 3.99 mmol, 1.00 equiv) intetrahydrofuran (10 mL), di-tert-butyl dicarbonate (959.2 mg, 4.40 mmol,1.10 equiv). This was followed by the addition of LiHMDS ((7.98 mL, 7.98mmol, 2.00 equiv, 1M in THF solution) dropwise with stirring at 0° C.The resulting solution was stirred at 25° C. overnight. The reaction wasthen quenched by the addition of 50 mL of NH₄Cl (sat. aq.). Theresulting solution was extracted with 3×20 mL of dichloromethane and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified on a silica gelcolumn with dichloromethane/methanol (100:1). This resulted in 740 mg(83%) of tert-butyl 2,5-dimethylpyridin-4-ylcarbamate as yellow oil.LCMS (method C, ESI): RT=0.83 min, m/z=223.0 [M+H]⁺.

Step 2: Synthesis of tert-butyl 2,5-dimethylpiperidin-4-ylcarbamate

Into a 30-mL high pressure tank reactor (70 atm), was placed a solutionof tert-butyl N-(2,5-dimethylpyridin-4-yl)carbamate (1.11 g, 4.99 mmol,1.00 equiv) in ethanol (25 mL), and 5% Rh/Al₂O₃. Then hydrogen wasintroduced into mixture and maintained at 70 atm. The resulting solutionwas stirred for 2 days at 70° C. The reaction mixture was cooled to 25°C. The solids were filtered out. The resulting mixture was concentratedunder vacuum. This resulted in 440 mg of tert-butyl2,5-dimethylpiperidin-4-ylcarbamate as black oil. LCMS (method A, ESI):RT=1.12 min, m/z=229.0 [M+H]⁺.

Step 3: Synthesis of tert-butyl1-((1R,4R)-4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-ylcarbamate

Into a 25-mL round-bottom flask was placed tert-butylN-(2,5-dimethylpiperidin-4-yl)carbamate (183.7 mg, 0.80 mmol, 1.10equiv),(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexane-1-carboxylicacid (200 mg, 0.73 mmol, 1.00 equiv), HATU (334 mg, 0.88 mmol, 1.20equiv). This was followed by the addition of TEA (370 mg, 3.66 mmol,5.00 equiv) by dropwise with stirring. The resulting solution wasstirred for 16 hours at 25° C. The resulting solution was diluted with100 mL of dichloromethane. The resulting mixture was washed with 3×30 mLof brine (sat. aq.). The mixture was dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was purified on a silica gelcolumn with dichloromethane/methanol (100:1). This resulted in 700 mg oftert-butyl1-((1R,4R)-4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-ylcarbamateas yellow oil. LCMS (method D, ESI): RT=0.91 min, m/z=484.0 [M+H]⁺.

Step 4: Synthesis of2-((1R,4R)-4-(4-Amino-2,5-dimethylpiperidine-1-carbonyl)cyclohexyl)isoindoline-1,3-dione hydrochloride

Into a 100-mL round-bottom flask was placed a solution of tert-butylN-(2,5-dimethyl-1-[[(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexyl]carbonyl]piperidin-4-yl)carbamate(700 mg, 1.45 mmol, 1.00 equiv) in dichloromethane (30 mL). To the abovehydrogen chloride was introduced. The resulting solution was stirred for30 min at 25° C. The resulting mixture was concentrated under vacuum.This resulted in 490 mg of2-((1R,4R)-4-(4-amino-2,5-dimethylpiperidine-1-carbonyl)cyclohexyl)isoindoline-1,3-dionehydrochloride as yellow oil. LCMS (method C, ESI): RT=1.11 min,m/z=384.0[M+H]⁺.

Step 5: Synthesis of5-Cyclopropyl-N-(1-((1R,4R)-4-(1,3-dioxoisoindolin-2-yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)isoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed2-[(1R,4R)-4-[(4-amino-2,5-dimethylpiperidin-1-yl)carbonyl]cyclohexyl]-2,3-dihydro-1H-isoindole-1,3-dione(838 mg, 2.19 mmol, 1.10 equiv), 5-cyclopropyl-1,2-oxazole-3-carboxylicacid (306 mg, 2.00 mmol, 1.00 equiv), HATU (912 mg, 2.40 mmol, 1.20equiv). This was followed by the addition of triethylamine (1 g, 9.88mmol, 5.00 equiv) dropwise with stirring. The resulting solution wasstirred at 25° C. overnight. The resulting solution was diluted with 100mL of dichloromethane. The resulting mixture was washed with 3×30 mL ofbrine (sat.). The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. The residue was purified on a silica gelcolumn with dichloromethane/methanol (100:1). This resulted in 500 mg of5-cyclopropyl-N-(2,5-dimethyl-1-[[(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexyl]carbonyl]piperidin-4-yl)-1,2-oxazole-3-carboxamideas yellow oil. LCMS (method C, ESI): RT=0.99 min, m/z=519.0[M+H]⁺

Step 6: Synthesis ofN-(1-((1R,4R)-4-Aminocyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed5-cyclopropyl-N-(2,5-dimethyl-1-[[(1R,4R)-4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)cyclohexyl]carbonyl]piperidin-4-yl)-1,2-oxazole-3-carboxamide(518 mg, 1.00 mmol, 1.00 equiv), water (1 mL) and propan-2-ol (6 mL).Then NaBH₄ (380 mg, 10.05 mmol, 10.00 equiv) was added batchwise. Theresulting solution was stirred for 16 hours at 25° C. This was followedby the addition of acetic acid (0.2 mL, 0.10 equiv) dropwise withstirring. The resulting solution was allowed to react with stirring for2 hour while the temperature was maintained at 80° C. in an oil bath.Then the reaction system was cooled. The pH value of the solution wasadjusted to 8 with sodium carbonate (50%, aq.). The resulting solutionwas extracted with 3×15 mL of dichloromethane and the organic layerscombined and dried over anhydrous sodium sulfate and concentrated undervacuum. The residue was purified on a silica gel column withdichloromethane/methanol (100:1). This resulted in 72.9 mg (19%) of5-cyclopropyl-N-(2,5-dimethyl-1-[[(1R,4R)-4-aminocyclohexyl]carbonyl]piperidin-4-yl)-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 6.40 (s, 1H), 4.89-3.70 (m,3H), 3.32-2.68 (m, 3H), 2.27-2.09 (m, 4H), 1.95-1.90 (m, 4H), 1.68-1.47(m, 4H), 1.34-1.11 (m, 5H), 0.92-1.01 (m, 5H) ppm. LCMS (method A, ESI):RT=1.32 min, m/z=389.0[M+H]⁺.

Step 7: Synthesis ofN-((2R,4S,5R)-1-((1r,4R)-4-Aminocyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

The crude product was purified by Chrial-HPLC with the followingconditions: Column, SHIMADZU-PDA(LC-08); mobile phase, Hex (0.2%IPA):EtOH=70:30; Detector, UV 254/220 nm. This resulted in 9.6 mg (24%)of (2S,4R,5S)-benzyl4-(5-cyclopropylisoxazole-3-carboxamido)-2,5-dimethylpiperidine-1-carboxylateas a white solid and 9.3 mg (23%) of (2R,4S,5R)-benzyl4-(5-cyclopropylisoxazole-3-carboxamido)-2,5-dimethylpiperidine-1-carboxylatewas obtained as a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 6.30 (s, 1H),4.76-3.60 (m, 3H), 3.10-2.90 (m, 1H), 2.85-2.75 (m, 1H), 2.61-2.45 (m,1H), 2.10-2.03 (m, 2H), 1.93-1.73 (m, 6H), 1.57-1.31 (m, 2H), 1.31-1.02(m, 7H), 0.89-0.84 (m, 5H) ppm. LCMS (method A, ESI): RT=1.31 min,m/z=389.0[M+H]⁺.

Example 9 Synthesis ofN-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 386)

Step 1: Synthesis of tert-butyl 4-amino-3-methylpiperidine-1-carboxylate

Into a 4-L round-bottom flask was placed methanol (3 L), formic acid(0.5 mL), HCOONH₄ (84 g, 1.33 mol, 40.00 equiv) and tert-butyl3-methyl-4-oxopiperidine-1-carboxylate (7 g, 32.82 mmol, 1.00 equiv).Then NaBH₃CN (4.1 g, 2.00 equiv) was added into batchwise. The resultingsolution was stirred for 2 hours at room temperature. The pH value ofthe solution was adjusted to 9 with sodium carbonate (5M in water). Theresulting mixture was concentrated under vacuum. The resulting solutionwas diluted with 50 mL of H₂O. The resulting solution was extracted with3×50 mL of ethyl acetate and the organic layers combined. This resultedin 7.0 g (99% crude) of tert-butyl4-amino-3-methylpiperidine-1-carboxylate as a white solid. ¹H NMR (300MHz, DMSO): 6.39 (brs, 2H), 3.95-3.75 (m, 1.5H), 3.70-3.60 (m, 0.5H),3.35-3.25 (brs, 0.5H), 3.05-2.95 (m, 0.5H), 2.90-2.63 (m, 1.5H),2.45-2.25 (brs, 0.5H), 2.10-2.00 (brs, 0.5H), 1.95-1.85 (m, 0.5H),1.65-1.45 (m, 1.5H), 1.35-1.25 (m, 0.5H), 1.38 (s, 9H), 1.20-1.10 (m,3H) ppm. LCMS (Method A, ESI): RT=1.02 min, m/z=215.0 [M+H]⁺.

Step 2: Synthesis of tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylate

Into a 250-mL round-bottom flask was placed tert-butyl4-amino-3-methylpiperidine-1-carboxylate (7 g, 32.66 mmol, 1.00 equiv),dichloromethane (100 mL), 5-cyclopropyl-1,2-oxazole-3-carboxylic acid(6.5 g, 42.45 mmol, 1.30 equiv), HATU (25.1 g, 104.13 mmol, 2.00 equiv).Then TEA (16.7 g, 165.04 mmol, 5.00 equiv) was added into mixturedropwise. The resulting solution was stirred for 2 h at roomtemperature. The resulting solution was concentrated under vacuum. Theresulting solution was diluted with 50 mL of H₂O. The resulting solutionwas extracted with 3×50 mL of ethyl acetate and the organic layerscombined. The resulting mixture was washed with 3×150 mL of brine(sat.). The mixture was dried over anhydrous sodium sulfate. The residuewas purified on a silica gel column with ethyl acetate/petroleum ether(1/5). This resulted in 6 g (52%) of tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylateasyellow solid. ¹H NMR (400 MHz, CD₃OD): 6.38 (s, 1H), 4.30-4.20 (m, 1H),4.20-4.05 (m, 1H), 3.80-3.76 (m, 1H), 3.56-3.45 (m, 1H), 3.29-3.20 (m,1H), 2.15-2.10 (m, 2H), 1.90-1.80 (m, 1H), 1.70-1.60 (m, 1H), 1.52 (s,9H), 1.20-1.16 (m, 2H), 1.05-0.85 (m, 5H) ppm. LCMS (Method A, ESI):RT=1.47 min, m/z=294.0 [M+H-56]⁺.

Step 3: Synthesis of (3S,4R)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylate

1.5 g of tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylatewas purified by Chrial-Prep-SFC with the following conditions: Column:CHIRALCEL OJ-3 (0.46*15 cm, 3 um); mobile phase, Hex:EtOH=90:10;Detector, 254 nm. This resulted in 240 mg (16%) of (3S,4R)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylateasa white solid. ¹H NMR (400 MHz, CD₃OD): 6.40 (s, 1H), 4.25-4.22 (m, 1H),4.00-3.88 (brs, 1H), 3.77-3.55 (brs, 1H), 3.24-3.23 (m, 2H), 2.20-2.15(m, 2H), 1.85-1.81 (m, 1H), 1.67-1.64 (m, 1H), 1.48 (s, 9H) 1.17-1.16(m, 2H), 1.05-0.98 (m, 5H) ppm.

Step 4: Synthesis of5-cyclopropyl-N-((3S,4R)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed (3S,4R)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-3-methylpiperidine-1-carboxylate(240 mg, 0.688 mmol, 1.00 equiv), dichloromethane (30 mL). To the abovehydrogen chloride was introduced. The resulting solution was stirred for1 h at room temperature. The resulting mixture was concentrated undervacuum. The resulting solution was diluted with 10 mL of water. The pHvalue of the solution was adjusted to 9 with sodium carbonate (5M inwater). The resulting solution was extracted with 3×10 mL of ethylacetate and the organic layers combined. This resulted in 150 mg (71%)of5-cyclopropyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. 1H NMR (400 MHz, CD₃OD): 6.40 (s, 1H), 4.28-4.26 (m,1H), 3.05-2.90 (brs, 1H), 2.90-2.70 (m, 3H), 2.20-2.05 (m, 2H),1.90-1.70 (m, 2H), 1.20-1.10 (m, 2H), 1.05-0.95 (m, 5H) ppm. LCMS(Method A, ESI): RT=0.97 min, m/z=250.0 [M+H].

Step 5: Synthesis of5-cyclopropyl-N-((3S,4R)-1-(3-(1,3-dioxoisoindolin-2-yl)propylsulfonyl)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed5-cyclopropyl-N-((3S,4R)-3-methylpiperidin-4-yl)isoxazole-3-carboxamide(150 mg, 0.60 mmol, 1.00 equiv), dichloromethane (20 mL) and TEA (180mg, 3.00 equiv). Then3-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propane-1-sulfonyl chloride (207mg, 0.72 mmol, 1.30 equiv) was added into the mixture dropwise at −20°C. The resulting solution was stirred for additional 24 hours at −20° C.The resulting mixture was concentrated under vacuum. The resultingmixture was triturated with 3×10 mL of EA. The solids were collected byfiltration. This resulted in 300 mg (100%) of5-cyclopropyl-N-[(3S,4R)-1-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-3-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. LCMS (method A, ESI): RT=1.40 min, m/z=501.0 [M+H].

Step 6: Synthesis ofN-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed5-cyclopropyl-N-[(3S,4R)-1-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-3-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide(300 mg, 0.60 mmol, 1.00 equiv), methanol (10 mL) and hydrazine hydrate(1 mL, 80% in water). The resulting solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under vacuum. Thecrude product (100 mg) was purified by Prep-HPLC with the followingconditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile PhaseA:Water/NH₄HCO₃ 10 mmol, Mobile Phase B: ACN; Flow rate: 30 mL/min;Gradient: 30% B to 85% B in 10 min; Detector, 254 nm This resulted in66.4 mg (30%) ofN-[(3R,4S)-1-[(3-aminopropane)sulfonyl]-3-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 6.40 (s, 1H), 4.24-4.20 (m,1H), 3.61-3.57 (m, 1H), 3.50-3.32 (m, 1H), 3.25-3.08 (m, 4H), 2.85-2.75(m, 2H), 2.30-2.14 (m, 2H), 2.00-1.89 (m, 3H), 1.80-1.70 (m, 1H),1.20-1.15 (m, 2H), 1.10-0.95 (m, 5H) ppm. LCMS (Method D, ESI): RT=2.11min, m/z=371.0 [M+H]⁺.

Example 10 Synthesis ofN-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride salt (Cpd. No. 181

Step 1: Synthesis of5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of argon was placedN-[9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide(250 mg, 0.91 mmol, 1.00 equiv), tetrahydrofuran (20 mL), the solutionwas cooled to −30° C., then LiHMDS (3 mL) was added and stirred for 30min at −30° C., and a solution of3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane-1-sulfonyl chloride(340 mg, 1.18 mmol, 1.30 equiv) in tetrahydrofuran (3 mL) was addedslowly. The resulting solution was stirred overnight at roomtemperature. The resulting solution was diluted with 10 mL of ethylacetate. The solids were filtered out. The resulting filtrate wasconcentrated under vacuum. The residue was purified on a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 200 mg(42%) of5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 8.50 (d, J=8.0 Hz, 1H),7.89-7.82 (m, 4H), 6.47 (s, 1H), 4.78-4.77 (m, 1H), 4.00-3.98 (m, 2H),3.70 (t, J=7.2 Hz, 2H), 3.20 (t, J=7.2 Hz, 2H), 2.20-2.16 (m, 1H),2.01-1.97 (m, 2H), 1.87-1.81 (m, 7H), 1.68 (d, J=8.4 Hz, 3H), 1.13-1.06(m, 2H), 0.93-0.89 (m, 2H) ppm. LCMS (method D, ESI): RT=1.48 min,m/z=527.1 [M+H]⁺.

Step 2: Synthesis ofN-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride salt

Into a 250-mL round-bottom flask, was placed5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide(200 mg, 0.38 mmol, 1.00 equiv), methanol (30 mL) and hydrazine hydrate(4 mL). The resulting solution was stirred for 1 h at room temperature.The resulting mixture was concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate. The crude product(200 mg) was further purified by Prep-HPLC with the followingconditions: Column, X Bridge C18, 19*150 mm, 5 um; mobile phase, MobilePhase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min;Detector, 254 nm. This resulted in 118.7 mg (72%) ofN-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. ¹H-NMR (300 MHz, CD₃OD): δ 6.40 (s, 1H),5.04-4.89 (m, 1H), 4.14 (brs, 2H), 3.24 (t, J=7.5 Hz, 2H), 3.13 (t,J=7.8 Hz, 2H), 2.20-1.77 (m, 13H), 1.17-1.12 (m, 2H), 0.99-0.94 (m, 2H)ppm. LCMS (method D, ESI): RT=1.35 min, m/z=397.0 [M+H]⁺.

Example 11 Synthesis of5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-methylpiperazine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide (Cpd. No. 279)

Into a 50-mL 3-necked round-bottom flask was placed5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride (200 mg, 0.70 mmol, 1.00 equiv), dichloromethane (10 mL)and TEA (353 mg, 3.49 mmol, 4.98 equiv). This was followed by theaddition of 4-methylpiperazine-1-sulfonyl chloride (166 mg, 0.84 mmol,1.19 equiv) at −20° C. The resulting solution was stirred at roomtemperature overnight. The reaction progress was monitored by LCMS. Theresulting mixture was washed with 2×5 mL of H₂O. The residue waspurified on a silica gel column with dichloromethane/methanol (20:1).This resulted in 136.3 mg (47%) of5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-methylpiperazine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (300 MHz, CD₃OD) δ: 6.37 (s, 1H), 4.14-4.11 (m,1H), 3.76-3.63 (m, 2H), 3.27-3.24 (m, 1H), 3.21 (t, 4H), 2.51 (t, 4H),2.32 (s, 3H), 2.19-2.13 (m, 1H), 2.01-1.95 (m, 2H), 1.85-1.65 (m, 2H),1.41 (d, 3H), 1.17-1.10 (m, 2H), 0.99-0.94 (m, 2H) ppm. LCMS (Method D,ESI): RT=1.74 min, m/z=412.0 [M+H]⁺.

Example 12 Synthesis ofN-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (Cpd. No. 348)

Step 1: Synthesis of tert-butyl4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxylate

Into a 250-mL round-bottom flask was placedN-[(2S,4S)-2-benzylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide(100 mg, 0.31 mmol, 1.00 equiv), dichloromethane (50 mL), HATU (353 mg,0.93 mmol, 3.02 equiv), TEA (157 mg, 1.55 mmol, 5.05 equiv),2-[1-[(tert-butoxy)carbonyl]piperidin-4-yl]acetic acid (75 mg, 0.31mmol, 1.00 equiv). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified on a silica gel column with ethyl acetate/petroleumether (1:1). This resulted in 130 mg (77%) of tert-butyl4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxylateas a yellow solid. LCMS (method A, ESI): RT=1.13 min. m/z=451.0[M-Boc]⁺.

Step 2: Synthesis ofN-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Into a 100-mL round-bottom flask was placed tert-butyl4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2-oxazole-3-amido)piperidin-1-yl]-2-oxoethyl]piperidine-1-carboxylate (130 mg, 0.24 mmol, 1.00 equiv) and1,4-dioxane (20 mL). Then hydrogen chloride was introduced into mixture.The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. This resulted in 64.0mg (56%) ofN-[(2S,4S)-2-benzyl-1-[2-(piperidin-4-yl)acetyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride as a white solid. ¹H NMR (400 MHz, D₂O): δ: 7.22-7.06 (m,5H), 6.30 (s, 1H), 4.70 (s, 0.5H), 4.38-4.30 (m, 0.5H), 4.30-4.15 (m,0.5H), 4.15-3.95 (m, 1H), 3.75-3.65 (m, 0.5H), 3.65-3.45 (m, 0.5H),3.30-3.01 (m, 3H), 3.01-2.90 (m, 0.5H), 2.90-2.70 (m, 3H), 2.45-2.35 (m,0.5H), 2.20-2.01 (m, 2H), 2.01-1.81 (m, 4H), 1.81-1.65 (m, 1.5H),1.65-1.51 (m, 1H), 1.51-1.41 (m, 1H), 1.41-1.39 (m, 1.5H), 1.10-1.01 (m,2H), 0.98-0.83 (m, 2.5H) ppm. LCMS (method D, ESI): RT=1.98 min.m/z=451.0 [M−HCl]⁺.

Example 13 Synthesis ofN-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 485)

Step 1: Synthesis ofN-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placedN-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide(200 mg, 0.62 mmol, 1.00 equiv), dichloromethane (5 mL), TEA (189 mg,1.87 mmol, 3.00 equiv). This was followed by the added of3-chloropropane-1-sulfonyl chloride (143 mg, 0.81 mmol, 1.30 equiv)dropwise at 0° C. The resulting solution was stirred overnight at 25° C.The solution was concentrated under vacuum. The residue was purified ona silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 240 mg (96%) ofN-[(1R,3r5S)-8-[(3-chloropropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamideas yellow oil. LCMS (method D, ESI): RT=0.97 min, m/z=402.0 [M+H]⁺.

Step 2: Synthesis of5-cyclopropyl-N-((1S,3r,5R)-8-(3-(1,3-dioxoisoindolin-2-yl)propylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placedN-[(1R,3S,5S)-8-[(3-chloropropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide(100 mg, 0.25 mmol, 1.00 equiv), N,N-dimethylformamide (5 mL),2-potassio-2,3-dihydro-1H-isoindole-1,3-dione (92 mg, 0.50 mmol, 2.00equiv). The resulting solution was stirred for 2 h at 80° C. Theresulting solution was extracted with 3×50 ml, of ethyl acetate and theorganic layers combined. The resulting mixture was washed with 3×70 mLof water. The mixture was dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 120 mg (94%) of5-cyclopropyl-N-[(1R,3r,5S)-8-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamideas a white solid. LCMS (method D, ESI): RT=0.98 min, m/z=513.0 [M+H]⁺.

Step 3: Synthesis ofN-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed5-cyclopropyl-N-[(1R,3r,5S)-8-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)propane]sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide(120 mg, 0.23 mmol, 1.00 equiv) and N₂H₄.H₂O (0.2 mL), methanol (7 mL).The resulting solution was stirred for 4 h at 25° C. The mixture wasconcentrated under vacuum and then dissolved in 50 mL ethyl acetate. Thesolids were filtered out. The filtrate was concentrated under vacuum.The crude product (100 mg) was purified by Prep-HPLC with the followingconditions (1#-Waters 2767-1): Column, X-bridge Prep phenyl 5 um, 19*150mmh Prep C012(T)186003581138241113.01; mobile phase, Phase A:water with0.5% NH₄HCO₃, Phase B:CH₃CN. Water with 0.5% NH₄HCO₃ and CH₃CN (30%CH₃CN up to 60% in 12 min, hold 95% in 1 min, down to 30% in 1 min);Detector, uv254 nm. This resulted in 50.7 mg (57%) ofN-[(1R,3r,5S)-8-[(3-aminopropane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD): 6.28 (s, 1H), 4.13 (s, 2H),4.07-4.04 (m, 1H), 3.07-3.03 (m, 2H), 2.69-2.66 (m, 2H), 2.21-2.15 (m,2H), 2.08-1.80 (m, 9H), 1.06-1.01 (m, 2H), 0.89-0.85 (m, 2H) ppm. LCMS(method D, ESI): RT=1.30 min, m/z=383.0 [M+H]⁺.

Example 14 Synthesis of5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(Cpd. No. 436

Step 1: Synthesis of5-cyclopropyl-N-((1R,3s,5S)-8-(vinylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 50-mL round-bottom flask was placedN-[(1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride (100 mg, 0.34 mmol, 1.00 equiv), TEA (102 mg, 1.01 mmol,3.00 equiv), dichloromethane (5 mL). This was followed by the dropwiseaddition of ethenesulfonyl chloride (61 mg, 0.48 mmol, 1.30 equiv) at 0°C. Then the resulting solution was stirred for 2 h at 25° C. Theresulting mixture was concentrated under vacuum. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether(3:1). This resulted in 100 mg (85%) of5-cyclopropyl-N-[(1R,3s,5S)-8-(ethenesulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamideas a light brown solid. LCMS (method D, ESI): RT=0.59 min, m/z=383.1[M+Na]⁺.

Step 2: Synthesis of5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 50-mL round-bottom flask was placed5-cyclopropyl-N-[(1R,3s,5S)-8-(ethenesulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide(90 mg, 0.26 mmol, 1.00 equiv), ethanol (10 mL), and pyrrolidine (0.2mL). The resulting solution was stirred at 25° C. overnight. Theresulting mixture was concentrated under vacuum. The crude product (89mg) was purified by Prep-HPLC with the following conditions (1#-Waters2767-1): Column, X-bridge Prep phenyl 5 um, 19*150 mmh PrepC012(T)186003581138241113.01; mobile phase, Phase A:water with 0.5%NH₄HCO₃, Phase B:CH₃CN. Water with 0.5% NH₄HCO₃ and CH₃CN (80% CH₃CN upto 95% in 13 min, hold 95% in 1 min, down to 80% in 1 min); Detector,uv254 nm. This resulted in 60.3 mg (56%) of5-cyclopropyl-N-[(1R,3s,5S)-8-[[2-(pyrrolidin-1-yl)ethane]sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): δ6.27 (s, 1H), 4.21-4.11 (m,2H), 4.02-4.08 (m, 1H), 3.22-3.18 (m, 2H), 2.84-2.79 (m, 2H), 2.52-2.49(m, 4H), 2.19-2.14 (m, 2H), 2.08-1.72 (m, 11H), 1.06-1.01 (m, 2H),0.89-0.85 (m, 2H) ppm. LCMS (method D, ESI): RT=1.36 min, m/z=423[M+H]⁺.

Example 15 Synthesis ofN-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 500)

Step 1: Synthesis of (2S)-tert-butyl4-amino-2-methylpiperidine-1-carboxylate

Into a 10-L round-bottom flask was placed methanol (5 L), HCOONH₄ (190g, 3.01 mol, 37.80 equiv), acetic acid (5 g, 83.26 mmol, 1.04 equiv) andtert-butyl (2S)-2-methyl-4-oxopiperidine-1-carboxylate (17 g, 79.71mmol, 1.00 equiv). Then NaBH₃CN (10 g, 159.13 mmol, 2.00 equiv) wasadded into the mixture slowly. The resulting solution was stirredovernight at 25° C. The resulting mixture was concentrated under vacuum.The resulting solution was diluted with 500 mL of ethyl acetate. Theresulting mixture was washed with 3×500 mL of brine (sat.). Theresulting organic phase was concentrated under vacuum. This resulted in15.5 g (91%) of tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylateas off-white oil. LCMS (method A, ESI): RT=1.21 min, m/z=215.1 [M+H]⁺.

Step 2: Synthesis of (2S)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

Into a 1 L round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed dichloromethane (500 mL), HOBT (15 g,111.01 mmol, 1.53 equiv), EDCI (20 g, 104.33 mmol, 1.44 equiv),5-cyclopropyl-1,2-oxazole-3-carboxylic acid (13.3 g, 86.85 mmol, 1.20equiv) and tert-butyl (2S)-4-amino-2-methylpiperidine-1-carboxylate(15.5 g, 72.33 mmol, 1.00 equiv). Then triethylamine (36 g, 355.77 mmol,4.92 equiv) was added dropwise. The resulting solution was stirred for 2hours at 25° C. The resulting mixture was concentrated under vacuum. Theresulting solution was diluted with 500 mL of ethyl acetate. Theresulting mixture was washed with 3×500 mL of water. The resultingorganic phase was concentrated under vacuum. The residue was purified ona silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 14 g (55%) of tert-butyl (2S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas light yellow oil. LCMS (method A, ESI): RT=2.05 min, m/z=350.2[M+H]⁺.

Step 3: Synthesis of (2S,4S)-tert-butyl4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-carboxylate

The diastereomeric product was further purified by Chiral-HPLC with thefollowing conditions: Column name: CHIRALPAK AD-H, 4.6*150 mm, 5 um,Co-Solvent: EtOH (0.1% DEA), % Co-Solvent: Hexane, 25.000, Detector: 220nm. The resulting solution was concentrated under vacuum. This resultedin 9.8 g (70%) of tert-butyl(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas colorless oil. ¹H-NMR (400 MHz, DMSO): δ 8.54-8.52 (m, 1H), 6.47 (s,1H), 3.94-3.87 (m, 2H), 3.57-3.53 (m, 1H), 3.32-3.26 (m, 1H), 2.20-2.16(m, 1H), 1.80-1.63 (m, 4H), 1.39 (s, 9H), 1.16-1.15 (m, 3H), 1.10-1.06(m, 2H), 0.93-0.89 (m, 2H) ppm and 3.3 g (24%) of tert-butyl(2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylateas a light yellow solid. ¹H-NMR (400 MHz, DMSO): δ 8.54-8.52 (m, 1H),6.46 (s, 1H), 4.54-4.30 (m, 1H), 4.28-4.04 (m, 1H), 4.00-3.68 (m, 1H),3.10-2.70 (m, 1H), 2.19-2.15 (m, 1H), 1.76-1.73 (m, 1H), 1.63-1.59 (m,2H), 1.39-1.35 (m, 10H), 1.13-1.08 (m, 5H), 1.00-0.82 (m, 2H) ppm.

Step 4: Synthesis of5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride

Into a 250-mL round-bottom flask was placed dichloromethane (100 mL) andtert-butyl(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(9.8 g, 28.05 mmol, 1.00 equiv). To the above hydrogen chloride (gas)was introduced into mixture. The resulting solution was stirred for 2hours at 25° C. The resulting mixture was concentrated under vacuum.This resulted in 8.6 g of5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride as a white solid. ¹HNMR (400 MHz, MeOD): δ 6.40 (s, 1H),4.24-4.10 (m, 1H), 3.55-3.45 (m, 1H), 3.40-3.35 (m, 1H), 3.19-3.15 (m,1H), 2.24-2.15 (m, 3H), 1.82-1.77 (m, 1H), 1.63-1.60 (m, 1H), 1.93-1.37(m, 3H), 1.21-1.13 (m, 2H), 1.00-0.96 (m, 2H) ppm. LCMS (method A, ESI):RT=1.13 min, m/z=250.1 [M−HCl+H]⁺.

Step 5: Synthesis ofN-((2S,4S)-1-(3-chloropropylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed dichloromethane (5 mL),triethylamine (121 mg, 1.20 mmol, 2.98 equiv) and5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide(100 mg, 0.40 mmol, 1.00 equiv). Then 3-chloropropane-1-sulfonylchloride (106 mg, 0.60 mmol, 1.49 equiv) was added dropwise at 0° C. Theresulting solution was stirred for 16 hours at 25° C. The resultingmixture was concentrated under vacuum. The residue was purified on asilica gel column with ethyl acetate/hexane (1:1). This resulted in 85mg (54%) ofN-[(2S,4S)-1-[(3-chloropropane)sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD): δ 6.38 (s, 1H), 4.13-4.01 (m,1H), 3.80-3.72 (m, 3H), 3.66-3.65 (m, 1H), 3.26-3.19 (m, 3H), 2.19-2.00(m, 3H), 2.04-1.98 (m, 2H), 1.77-1.70 (m, 2H), 1.43 (d, J=6.8 Hz, 3H),1.00-0.97 (m, 2H), 1.16-1.12 (m, 2H) ppm. LCMS (method A, ESI): RT=1.37min, m/z=390.0 [M+H]⁺.

Step 6: Synthesis ofN-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 10 mL round-bottom flask was placed 1,4-dioxane (3 mL),N-[(2S,4S)-1-[(3-chloropropane)sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide(84 mg, 0.22 mmol, 1.00 equiv), and phenylmethanamine (274 mg, 2.56mmol, 11.87 equiv). The resulting solution was stirred for 16 hours at100° C. The resulting mixture was concentrated under vacuum. The residuewas purified on a silica gel column with ethyl acetate/hexane (1:1).This resulted in 30.1 mg (30%) ofN-[(2S,4S)-1-[[3-(benzylamino)propane]sulfonyl]-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CD₃OD): δ 7.37-7.29 (m, 5H), 6.38 (s,1H), 4.13-4.01 (m, 1H), 3.82 (s, 2H), 3.80-3.78 (m, 1H), 3.62 (d, J=3.2Hz, 1H), 3.18-3.11 (m, 3H), 2.78 (t, J=3.2 Hz, 2H), 2.18-2.16 (m, 1H),2.04-1.97 (m, 4H), 1.77-1.70 (m, 2H), 1.43 (d, J=6.8 Hz, 3H), 1.00-0.97(m, 2H), 1.16-1.12 (m, 2H) ppm. LCMS (method A, ESI): RT=1.48 min,m/z=461.3 [M+H]⁺.

Example 16 Synthesis of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2-morpholinoethylamino)pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamidedihydrochloride (Cpd. No. 458)

Step 1: Synthesis ofN-((2S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole-3-carboxamidehydrochloride (200 mg, 0.69 mmol, 1.00 equiv). Then triethylamine (210mg, 2.09 mmol, 3.00 equiv) was added into dropwise. The reaction mixturewas cooled to 0° C., then 6-chloropyridine-3-sulfonyl chloride (220 mg,1.04 mmol, 1.50 equiv) was added dropwise. The resulting solution wasstirred at room temperature for 15 h. The resulting mixture was washedby water (3×10 ml), dried over Na₂SO₄ and concentrated under vacuum.This resulted in 296 mg (97%) ofN-((2S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamideas light yellow solid. LCMS (method D, ESI): RT=1.47 min, m/z=425[M+H]⁺.

Step 2: Synthesis of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2-morpholinoethylamino)pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamidedihydrochloride

Into a 50-mL round-bottom flask was placedN-42S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(296 mg, 0.69 mmol, 1.00 equiv), 2-morpholinoethanamine (226 mg, 1.74mmol, 2.4 equiv) and 1,4-dioxane (5 mL). The resulting solution wasstirred at 80° C. for 15 h. The resulting mixture was purified bypre-HPLC. Column: X Select C18, 19×150 mm, 5 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 5%B to 45% B in 11.5 min; 254 nm. This resulting eluent was acidified byhydrochloric acid (6Nand concentrated resulting in 102.80 mg (28%) of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2-morpholinoethylamino)pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamidedihydrochloride as light yellow solid. ¹H-NMR (300 MHz, D₂O): δ 8.44 (s,1H), 7.94 (d, J=9.0 Hz, 1H), 6.85 (d, J=9.0 Hz, 1H), 6.29 (s, 1H),4.14-3.08 (m, 16H), 2.12-2.08 (m, 1H), 1.97-1.86 (m, 2H), 1.64-1.79 (m,2H), 1.26-1.24 (d, J=6.0 Hz, 3H), 1.08-1.05 (m, 2H), 0.99-0.74 (m, 2H)ppm. LCMS (method D, ESI): RT=2.37 min, m/z=519.0 [M+H]⁺.

Example 17 Synthesis of5-cyclopropyl-N-((2S,4S)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(Cpd. No. 417) and5-cyclopropyl-N-((2R,4R)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(Cpd. No. 418)

Step 1: Synthesis of tert-butyl4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate

To a solution of cis tert-butyl 4-amino-2-methylpiperidine-1-carboxylate(1 g, 4.67 mmol) and DIPEA (2.44 ml, 14 mmol) in DMF (25 ml) was added5-cyclopropyl-1,2-oxazole-3-carboxylic acid (0.86 g, 5.6 mmol) followedby HATU (2.31 g, 6.07 mmol). The reaction was stirred at rt. LCMSanalysis after ˜1 h showed a trace of SM and mainly product (72%, 1.33min, MNa+.=371.95). The reaction was poured into water (100 ml) and theproduct was extracted with EtOAc (3×50 ml). The combined organic layerswere washed with water (2×50 ml), brine (50 ml), dried over Na₂SO₄,filtered and concentrated. The red oily residue was purified by Isoleraover SiO₂ (100 g), eluting with a gradient of EtOAc in heptane from 5 to50% to yield 1.55 g (95%) of the amide as an amber viscous. TLC (25%EtOAc in Hept), rf:0.30. ¹H NMR (500 MHz, Chloroform-d) δ 6.85 (d, J=6.8Hz, 1H), 6.31 (s, 1H), 4.21 (hept, J=6.8, 6.1 Hz, 2H), 3.85 (ddd,J=14.0, 5.5, 3.1 Hz, 1H), 3.13 (ddd, J=14.3, 11.9, 3.9 Hz, 1H), 2.06(ddd, J=8.4, 4.9, 3.4 Hz, 1H), 2.02-1.91 (m, 2H), 1.74-1.66 (m, 2H),1.45 (s, 9H), 1.25 (d, J=7.2 Hz, 3H), 1.13-1.08 (m, 2H), 1.00-0.94 (m,2H). LCMS analysis (METCR1673 Generic 2 minutes), 100%, 1.33 min,[MNa]^(+.)=372.00.

Step 2: Synthesis of5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3-carboxamidehydrochloride

A solution of tert-butyl4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate(1.55 g, 4.44 mmol) in DCM (50 ml) was treated with 4M HCl in dioxane(15 ml) at rt for ˜4 h. LCMS analysis showed complete reaction. Thesolvent was evaporated to dryness to yield 1.12 g (88%) of the amine asHCl salt as a white solid. ¹H NMR (250 MHz, Methanol-d4) δ 6.38 (s, 1H),4.17 (tt, J=11.9, 4.1 Hz, 1H), 3.53-3.34 (m, 2H), 3.14 (td, J=13.3, 3.1Hz, 1H), 2.28-2.08 (m, 3H), 1.94-1.52 (m, 2H), 1.37 (d, J=6.5 Hz, 3H),1.20-1.09 (m, 2H), 1.00-0.91 (m, 2H). LCMS analysis (METCR1673 Generic 2minutes), 100%, ˜0.45 min, [MH−HCl]⁺=250.00.

Step 3: Synthesis of benzyl4-({[4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidin-1-yl]sulfonyl}methyl)piperidine-1-carboxylate

To a solution of5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3-carboxamidehydrochloride (920 mg, 3.22 mmol) in DCM (40 ml) was added DIPEA (3.37ml, 19.3 mmol) followed by benzyl4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (1175 mg, 3.54 mmol)as a solution in DCM (10 ml) and the reaction was left at rt overnight.The reaction was diluted with DCM (100 ml) and washed with water (50 ml)and brine (50 ml). The combined aqueous layers were back-extracted withEtOAc (2×25 ml). The combined organic layers were dried over Na₂SO₄,filtered and concentrated. The residue was purified by Isolera over SiO₂(100 g), dry loaded and eluted with a gradient of EtOAc in heptane from12 to 100% then with a gradient of MeOH in EtOAc from 0 to 20% to yield0.92 g (47%) of sulfonamide as a white solid. TLC (2.5% MeOH in DCM),rf:0.30. ¹H NMR (500 MHz, Chloroform-d) δ 7.40-7.28 (m, 5H), 6.77 (d,J=7.4 Hz, 1H), 6.32 (s, 1H), 5.12 (s, 2H), 4.20 (ddt, J=16.0, 7.7, 4.5Hz, 3H), 3.76-3.63 (m, 2H), 3.21 (ddd, J=13.5, 7.4, 3.8 Hz, 1H), 2.83(hept, J=6.4 Hz, 4H), 2.24-1.90 (m, 6H), 1.79-1.69 (m, 2H), 1.44 (d,J=6.9 Hz, 3H), 1.33-1.22 (m, 2H), 1.16-1.09 (m, 2H), 1.01-0.96 (m, 2H).LCMS analysis (METCR1673 Generic 2 minutes), 100%, 1.38 min,[MH]^(+.)=545.00.

Step 4: Synthesis of5-cyclopropyl-N-[2-methyl-1-(piperidin-4-ylmethanesulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide

To a solution of benzyl4-({[4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidin-1-yl]sulfonyl}methyl)piperidine-1-carboxylate(90%, 917 mg, 1.52 mmol) in MeCN (50 ml) and DCM (5 ml) was added TMS-I(647 μl, 4.55 mmol) at rt for 1 h. The solution was then added onto 50ml of 0.5M HCl in MeOH and the mixture was stirred at rt for anadditional ˜2 h. The solvent was evaporated and the residue was purifiedby Isolute SCX-2 (10 g cartridge) eluted with MeOH (15×10 ml) then with7N NH₃ in MeOH to yield 636 mg (96%) of5-cyclopropyl-N-(2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamideas a white solid. ¹H NMR (500 MHz, Chloroform-d) δ 6.79 (d, J=7.2 Hz,1H), 6.32 (s, 1H), 4.20 (ddq, J=12.0, 7.7, 4.6 Hz, 1H), 3.74-3.64 (m,2H), 3.21 (ddd, J=13.4, 7.4, 3.8 Hz, 1H), 3.09 (d, J=12.3 Hz, 2H), 2.83(h, J=6.9, 6.3 Hz, 2H), 2.70-2.63 (m, 2H), 2.06 (dddt, J=17.4, 13.0,8.2, 5.1 Hz, 4H), 1.94 (d, J=12.5 Hz, 2H), 1.73 (dt, J=13.7, 6.3 Hz,5H), 1.45 (d, J=6.9 Hz, 3H), 1.37-1.26 (m, 2H), 1.14-1.09 (m, 2H),1.00-0.96 (m, 2H). LCMS analysis (METCR1673 Generic 2 minutes), 94%,0.90 min, [MH]^(+.)=411.00.

Step 5: Chiral separation of5-cyclopropyl-N-[2-methyl-1-(piperidin-4-ylmethanesulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide

The racemic mixture of5-cyclopropyl-N-(2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(94%, 636 mg, 1.46 mmol) of the cis isomers were purified by chiralseparation using the following conditions: 25% Methanol+0.1% DEA:80% CO2with Chiralpak AD-H 25 cm column at 15 ml/min. 254 mg (43%) of racemicmixture was recovered. 118 mg (20%) of5-cyclopropyl-N-((2S,4S)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(arbitrarily assigned as (S,S)-isomer) was isolated at 100% ee, having aretention time on chiral column of 3.21 min. ¹H NMR (500 MHz,Methanol-d4) δ 6.36 (s, 1H), 4.10 (tt, J=9.1, 4.6 Hz, 1H), 3.77 (ddd,J=13.4, 6.7, 4.0 Hz, 1H), 3.63-3.55 (m, 1H), 3.15 (ddd, J=13.2, 8.5, 3.7Hz, 1H), 3.07-3.02 (m, 2H), 3.01-2.93 (m, 2H), 2.63 (td, J=12.5, 2.7 Hz,2H), 2.15 (tt, J=8.5, 5.0 Hz, 1H), 2.12-1.90 (m, 5H), 1.77-1.67 (m, 2H),1.41 (d, J=6.7 Hz, 3H), 1.33 (qd, J=12.0, 3.6 Hz, 2H), 1.16-1.10 (m,2H), 0.98-0.94 (m, 2H). LCMS analysis (METCR1416 Hi res 7 min), 100%,2.74 min, [MH]^(+.)=411.00. 119 mg (19%) of5-cyclopropyl-N-((2R,4R)-2-methyl-1-((piperidin-4-ylmethyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(arbitrarily assigned as (R,R) isomer) was isolated at 96% ee, having aretention time on chiral column of 4.77 min. ¹H NMR (500 MHz,Methanol-d4) δ 6.36 (s, 1H), 4.10 (tt, J=9.1, 4.6 Hz, 1H), 3.77 (ddd,J=13.4, 6.7, 4.0 Hz, 1H), 3.63-3.55 (m, 1H), 3.15 (ddd, J=13.0, 8.5, 3.7Hz, 1H), 3.04 (d, J=12.7 Hz, 2H), 3.02-2.93 (m, 2H), 2.64 (td, J=12.5,2.6 Hz, 2H), 2.15 (tt, J=8.4, 5.0 Hz, 1H), 2.12-1.91 (m, 5H), 1.77-1.67(m, 2H), 1.41 (d, J=6.7 Hz, 3H), 1.33 (qd, J=12.0, 3.1 Hz, 2H),1.15-1.11 (m, 2H), 0.98-0.94 (m, 2H). LCMS analysis (METCR1416 Hi res 7min), 100%, 2.74 min, [MH]^(+.)=410.95.

Example 18 Synthesis of5-cyclopropyl-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl) isoxazole-3-carboxamide (Cpd. No. 543)

Step 1: Synthesis of benzyl4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 25-mL round-bottom flask was placedN-((1S,3R,5R)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (80 mg, 0.27 mmol, 1.00 equiv), dichloromethane (5 mL),TEA (81 mg, 0.80 mmol, 3.00 equiv), and 4-dimethylaminopyridine (33 mg,0.27 mmol, 1.00 equiv). This was followed by the addition of benzyl4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (140 mg, 0.42 mmol,1.50 equiv) dropwise at 0° C. The resulting solution was stirred for 4 hat 25° C. The reaction was quenched with water/ice (20 mL) and extractedwith EA (20 mL, three times). The organic extracts were combined andwashed with brine (20 mL), then dried over with Na₂SO₄. Afterevaporation, the residue was chromatographed on a silica gel column withethyl acetate/petroleum ether (2:3). This resulted in 70 mg (47%) ofbenzyl 4-(((1S, 3R,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl) methyl) piperidine-1-carboxylate as a yellow solid.LCMS (method A, ESI): RT=1.09 min, m/z=557.0 [M+H]⁺.

Step 2: Synthesis of 5-cyclopropyl-N-((1R, 3rR,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed benzyl 4-(((1 S, R,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl) methyl) piperidine-1-carboxylate (70 mg, 0.13 mmol,1.00 equiv) and hydrochloric acid (12N, 3 mL). The resulting solutionwas stirred for 2 h at 25° C. The residue was concentrated under vacuum.The crude product (32.9 mg) was purified by Flash-Prep-HPLC with thefollowing conditions (IntelFlash-1): Column, silica gel; mobile phase:(phase A: 0.5% NH₄HCO₃ in H₂O, phase B: CH₃CN) B/A=5% increasing toB/A=80% within 15 min; Detector, UV 254 nm. This resulted in 14.4 mg(27%) of 5-cyclopropyl-N-((1S, 3R,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1] octan-3-yl)isoxazole-3-carboxamide as a white solid. ¹H-NMR (400 MHz, CD₃OD): δ6.48(s, 1H), 4.56 (s, 2H), 4.20-4.16 (m, 1H), 3.34-3.02 (m, 4H), 2.66-2.59(m, 2H), 2.31-1.92 (m, 12H), 1.34-1.30 (m, 2H), 1.18-1.13 (m, 2H),1.01-0.97 (m, 2H) ppm. LCMS (method A, ESI): RT=1.36 min, m/z=423.3[M+H]⁺.

Example 19 Synthesis ofN-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidetrifluoroacetic acid (Cpd. No. 529)

Step 1: Synthesis of 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl chloride

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed dichloromethane (30 mL) and sulfurylchloride (5.1 g, 37.79 mmol, 1.08 equiv). This was followed by theaddition of a solution of 1,4-dioxa-8-azaspiro[4.5]decane (5 g, 34.92mmol, 1.00 equiv) and 4-dimethylaminopyridine (4.27 g, 34.95 mmol, 1.00equiv) in dichloromethane (10 mL) dropwise with stirring at −78° C. Theresulting solution was stirred for 4 hours at 25° C. The resultingmixture was concentrated under vacuum. The residue was chromatographedon a silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 4.2 g (50%) of 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonylchloride as a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 4.02 (s, 4H), 3.51(s, 4H), 1.94-1.91 (m, 4H) ppm.

Step 2: Synthesis of5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide

Into a 50-mL round-bottom flask was placed dichloromethane (15 mL),triethylamine (500 mg, 4.94 mmol, 4.71 equiv), and5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride (300 mg, 1.05 mmol, 1.00 equiv). This was followed by theaddition of a solution of 1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonylchloride (700 mg, 2.90 mmol, 2.76 equiv) in dichloromethane (5 mL)dropwise with stirring at −78° C. The resulting solution was stirred for16 hours at 25° C. The reaction mixture was washed with brine (sat. aq.,3×10 mL) and the organic layer concentrated under vacuum. The residuewas chromatographed on a silica gel column with ethyl acetate/petroleumether (3:7). This resulted in 300 mg (63%) of5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 6.82 (d, J=7.2 Hz, 1H),6.34 (s, 1H), 4.24-4.22 (m, 1H), 3.98 (s, 4H), 3.73-3.70 (m, 1H),3.63-3.60 (m, 1H), 3.35-3.27 (m, 5H), 2.11-2.00 (m, 3H), 1.80-1.73 (m,6H), 1.45 (d, J=6.8 Hz, 3H), 1.16-1.12 (m, 2H), 1.02-0.98 (m, 2H) ppm.LCMS (method D, ESI): RT=1.91 min, m/z=455.5 [M+H]⁺.

Step 3: Synthesis of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-oxopiperidin-1-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placed THF (10 mL),5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8-azaspiro[4.5]decane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide(300 mg, 0.66 mmol, 1.00 equiv) and hydrochloric acid (2N, 5 mL). Theresulting solution was stirred for 16 hour at 25° C. The pH value of thesolution was adjusted to 8 with Na₂CO₃ (sat. aq.). The resulting mixturewas concentrated under vacuum. The resulting mixture was diluted with 10mL of DCM. The solids were filtered off yielding 250 mg (92%) of5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-oxopiperidine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H NMR (400 MHz, CDCl₃) δ: 6.83 (d, J=6.38 Hz, 1H),6.34 (s, 1H), 4.26-4.24 (m, 1H), 3.72-3.66 (m, 2H), 3.59-3.56 (m, 4H),3.34-3.32 (m, 1H), 2.60-2.56 (m, 4H), 2.11-2.04 (m, 3H), 1.82-1.76 (m,2H), 1.48 (d, J=6.8 Hz, 3H), 1.15-1.12 (m, 2H), 1.02-1.00 (m, 2H) ppm.LCMS (method D, ESI): RT=1.32 min, m/z=411.2 [M+H]⁺.

Step 4: Synthesis ofN-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamidetrifluoroacetic acid

Into a 250-mL round-bottom flask was placed methanol (100 mL),5-cyclopropyl-N-[(2S,4S)-2-methyl-1-(4-oxopiperidine-1-sulfonyl)piperidin-4-yl]-1,2-oxazole-3-carboxamide(60 mg, 0.15 mmol, 1.00 equiv), and ammonium formate (500 mg, 7.93 mmol,54.25 equiv). Then NaBH₃CN (30 mg, 0.48 mmol, 3.27 equiv) was added at0° C. The resulting solution was stirred for 16 hours at 25° C. Thereaction mixture was concentrated under vacuum and the residue dilutedwith 20 mL of dichloromethane. The resulting mixture was washed withbrine (sat. aq., 2×10 mL). The organic layer was concentrated undervacuum and the crude product purified by Prep-HPLC with the followingconditions (1#-Pre-HPLC-005(Waters)): Column, Atlantis Prep OBD T3Column, 19*150 mm, 5 um, mobile phase, water with 0.05% TFA and CH₃CN(up to 3.0% in 10 min, up to 100.0% in 1 min, hold 100.0% in 1 min);Detector, UV 254 nm. This resulted in 26.4 mg (34%) ofN-[(2S,4S)-1-(4-aminopiperidine-1-sulfonyl)-2-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidetrifluoroacetate as a white solid. ¹H NMR (400 MHz, CD₃OD) δ: 6.38 (s,1H), 4.13-4.05 (m, 1H), 3.80-3.77 (m, 3H), 3.76-3.74 (m, 1H), 3.33-3.23(m, 2H), 2.93 (t, J=12.4 Hz, 2H), 2.19-2.15 (m, 1H), 2.07-1.95 (m, 4H),1.82-1.67 (m, 4H), 1.42 (d, J=6.8 Hz, 3H), 1.18-1.13 (m, 2H), 1.00-0.97(m, 2H) ppm. LCMS (method A, ESI): RT=1.71 min, m/z=412.5 [M-TFA+H]⁺.

Example 20 Synthesis ofN-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 541)

Step 1: Synthesis ofN-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed5-cyclopropyl-N-[(2S,4S)-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamidehydrochloride (1 g, 3.50 mmol, 1.00 equiv) and dichloromethane (10 mL).This was followed by the dropwise addition of TEA (1.1 g, 10.87 mmol,3.11 equiv) with stirring at 0° C. To this was added4-bromobenzene-1-sulfonyl chloride (900 mg, 3.52 mmol, 1.01 equiv) inseveral batches at 0° C. The resulting solution was stirred at roomtemperature for overnight. The reaction mixture was diluted with 10 mLof H₂O and extracted with 3×20 mL of dichloromethane. Theorganic layerswere combined and dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was chromatographed on a silica gel columnwith ethyl acetate/petroleum ether (1:10-1:2). This resulted in 1.6 g(98%) ofN-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.75-7.64 (m, 4H), 6.75 (d,J=6.4 Hz, 1H), 6.32 (s, 1H), 4.17-4.03 (m, 1H), 3.80-3.69 (m, 1H),3.67-3.53 (m, 1H), 3.30-3.18 (m, 1H), 2.12-2.03 (m, 1H), 2.03-1.92 (m,2H), 1.82-1.66 (m, 2H), 1.33 (d, J=6.8 Hz, 3H), 1.19-1.09 (m, 2H),1.03-0.95 (m, 2H) ppm. LCMS (Method A, ESI): RT=1.54 min, m/z=468.0[M+H]⁺.

Step 2: Synthesis of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2-yl)phenylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placedN-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(1 g, 2.14 mmol, 1.00 equiv), Pd(dppf)Cl₂ (160 mg, 0.22 mmol, 0.10equiv), K₂CO₃ (880 mg, 6.32 mmol, 2.96 equiv),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (540 mg, 3.21mmol, 1.51 equiv), 1,4-dioxane (10 mL) and water (1 mL). The resultingsolution was stirred at 90° C. overnight. The reaction mixture wasdiluted with 10 mL of H₂O and extracted with 3×50 mL of ethyl acetate.Theorganic layers were combined and dried over anhydrous sodium sulfateand concentrated under vacuum. The residue was chromatographed on asilica gel column with ethyl acetate/petroleum ether (1:10-1:2). Thisresulted in 480 mg (52%) of5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2-yl)phenylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamideas a light yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.76 (d, J=8.7 Hz,2H), 7.58 (d, J=8.7 Hz, 2H), 6.73 (d, J=6.6 Hz, 1H), 6.30 (s, 1H), 5.48(s, 1H), 5.24 (s, 1H), 4.17-3.98 (m, 1H), 3.81-3.68 (m, 1H), 3.61-3.47(m, 1H), 3.28-3.12 (m, 1H), 2.18 (s, 3H), 2.11-1.92 (m, 3H), 1.79-1.60(m, 2H), 1.33 (d, J=6.6 Hz, 3H), 1.16-1.05 (m, 2H), 1.02-0.91 (m, 2H)ppm. LCMS (Method D, ESI): RT=1.61 min, m/z=430.0 [M+H]⁺.

Step 3: Synthesis ofN-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2-yl)phenylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide(480 mg, 1.12 mmol, 1.00 equiv), 2-chloroacetonitrile (1.67 g, 22.12mmol, 19.79 equiv), and acetic acid (28 mL). After cooling to 0° C.sulfuric acid (98%, 7 mL) was added dropwise. The resulting solution wasstirred at room temperature overnight. The reaction mixture was dilutedwith of ice-water and the pH of the solution was adjusted to 7 withsodium carbonate (sat. aq.). The resulting solution was extracted with3×50 mL of dichloromethane and the organic layers combined and driedover anhydrous sodium sulfate. The residue was chromatographed on asilica gel column with dichloromethane/methanol (20:1). This resulted in580 mg (99%) ofN-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (300 MHz, CD₃OD): δ 7.78 (d, J=8.7 Hz, 2H),7.62 (d, J=8.7 Hz, 2H), 6.34 (s, 1H), 4.09-3.99 (m, 3H), 3.95-3.80 (m,2H), 3.17-3.00 (m, 1H), 2.20-2.08 (m, 1H), 2.03-1.79 (m, 2H), 1.77-1.56(m, 8H), 1.33 (d, J=6.6 Hz, 3H), 1.19-1.09 (m, 2H), 1.00-0.91 (m, 2H)ppm. LCMS (Method D, ESI): RT=0.97 min, m/z=523.0 [M+H]⁺.

Step 4: Synthesis ofN-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placedN-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(150 mg, 0.29 mmol, 1.00 equiv), acetic acid (0.3 mL), ethanol (1.5 mL)and thiourea (26 mg, 0.34 mmol, 1.19 equiv). The resulting solution wasstirred at 85° C. overnight. The reaction mixture was concentrated undervacuum and the residue diluted with 10 mL of H₂O. The resulting solutionwas extracted with 3×5 mL of ethyl acetate and the organic layerscombined. The combined extracts were concentrated under vacuum and thecrude product (98 mg) was purified by Prep-HPLC with the followingconditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/10 mmol/L NH₄HCO₃, Mobile Phase B: MeOH; Flow rate: 30 mL/min;Gradient: 45% B to 75% B in 06 min; 254 nm. 100 mL product was obtained.This resulted in 24 mg (19%) ofN-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 7.85-7.71 (m, 4H), 6.35 (s,1H), 3.92-3.80 (m, 2H), 3.41-3.33 (m, 1H), 3.16-3.07 (m, 1H), 2.21-2.10(m, 1H), 2.00-1.91 (m, 1H), 1.91-1.82 (m, 1H), 1.76-1.62 (m, 2H), 1.54(s, 6H), 1.34 (d, J=6.4 Hz, 3H), 1.19-1.09 (m, 2H), 1.00-0.91 (m, 2H)ppm. LCMS (Method B, ESI): RT=1.71 min, m/z=447.0 [M+H]⁺.

Example 21 Synthesis of5-cyclopropyl-N-[(1R,3r,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide(Cpd. No. 528)

Into a 50-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed5-cyclopropyl-N-[(1R,3R,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamide(68 mg, 0.16 mmol, 1.00 equiv), methanol (2 mL), and4,4,4-trifluorobutanal (41 mg, 0.33 mmol, 2.00 equiv). Then NaBH₃CN (51mg, 5.00 equiv) was added at 0° C. The resulting solution was stirredfor 6 h at room temperature. The reaction mixture was concentrated undervacuum. The residue was dissolved in DCM (10 mL) and washed withsaturated brine (10 mL). The organic phase was collected andconcentrated under vacuum. The crude product was purified by Prep-HPLCwith the following conditions (Prep-HPLC-019): Column, XBridge Prep C18OBD Column, 19*100 mm 5 um 13 nm; mobile phase, Water with 10mmolNH₄HCO₃ and MeCN (30.0% MeCN up to 60.0% in 6 min); Detector, UV254/220 nm. This resulted in 23.6 mg (28%) of5-cyclopropyl-N-[(1R,3R,5S)-8-([[1-(4,4,4-trifluorobutyl)piperidin-4-yl]methane]sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): 6.39 (s, 1H), 4.25 (s, 2H),4.17 (t, J=6.8 Hz, 1H), 3.07 (d, J=5.6 Hz, 2H), 2.96 (d, J=11.6 Hz, 2H),2.43 (t, J=7.6 Hz, 2H), 2.31-1.97 (m, 16H), 1.81-1.74 (m, 2H), 1.46 (q,J=12.4 Hz, 2H), 1.18-1.13 (m, 2H), 1.00-0.95 (m, 2H) ppm. LCMS (methodA, ESI): RT=1.52 min, m/z=533.4 [M+H]⁺.

Example 22 Synthesis ofN-((2S,4S)-1-(3,8-diaza-bicyclo[3.2.1]octan-8-ylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 555)

Step 1: Synthesis of(2S,4S)-4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidine-1-sulfonylchloride

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed solution of sulfuryl chloride(242 mg, 1.79 mmol, 1.50 equiv) in dichloromethane (10 mL) at −70° C. Tothis was added a solution of DIEA (621 mg, 4.81 mmol, 4.00 equiv) and5-cyclopropyl-N-(3-methylpiperazin-1-yl)-1,2-oxazole-3-carboxamide (300mg, 1.20 mmol, 1.00 equiv) in dichloromethane (5 mL) dropwise withstirring at −70° C. The resulting solution was stirred for 30 min at−70° C. in a dry ice bath. The reaction mixture was concentrated undervacuum and the residue was chromatographed on a silica gel column withethyl acetate/petroleum ether (1:4). The fractions containing productwere combined and concentrated under vacuum. This resulted in 350 mg(84%) of4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperazine-1-sulfonylchloride as a white solid. LCMS (method D, ESI): RT=0.98 min, m/z=348[M+H]⁺.

Step 2: Synthesis of tert-butyl8-((2S,4S)-4-(5-cyclopropylisoxazole-3-carboxamido)-2-methylpiperidin-1-ylsulfonyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylate

Into a 50-mL round-bottom flask was placed tert-butyl3,8-diazabicyclo[3.2.1]octane-3-carboxylate (366.6 mg, 1.73 mmol, 1.50equiv), dichloromethane (20 mL), DIEA (298 mg, 2.31 mmol, 2.00 equiv),and 4-dimethylaminopyridine (14 mg, 0.11 mmol, 0.10 equiv). To this wasadded a solution of(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonylchloride (400 mg, 1.15 mmol, 1.00 equiv) in dichloromethane (2 mL)dropwise with stirring at 0° C. under nitrogen. The resulting solutionwas stirred overnight at room temperature. After concentration, theresidue was chromatographed on a silica gel column with ethylacetate/petroleum ether (1/10-1/5). This resulted in 550 mg (91%) oftert-butyl8-[(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylateas colorless oil. LCMS (method D, ESI): RT=1.26 min, m/z=524.3 [M+H]⁺.

Step 3: Synthesis of5-cyclopropyl-N-[(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide

Into a 50-mL round-bottom flask was placed tert-butyl8-[(2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-sulfonyl]-3,8-diazabicyclo[3.2.1]octane-3-carboxylate(550 mg, 1.05 mmol, 1.00 equiv), dichloromethane (20 mL) andtrifluoroacetic acid (4 mL). The resulting solution was stirred for 2.5h at room temperature. The reaction mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions: Column, Sunfire C18 19*150, mobile phase, CH₃CN:NH₄CO₃/H₂O(10 mmol/L)=20%-55%, 20 min, Detector UV 254 nm. This resulted in 355.4mg (80%) of5-cyclopropyl-N-[(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane-8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 6.90-6.71 (m, 1H), 6.32 (s,1H), 4.28-4.15 (m, 1H), 3.78-3.68 (m, 1H), 3.67-3.50 (m, 3H), 3.4-3.28(m, 2H), 3.27-3.15 (m, 1H), 3.10-3.00 (m, 2H), 2.20-2.00 (m, 4H),1.89-1.69 (m, 6H), 1.50-1.39 (m, 3H), 1.20-1.06 (m, 2H), 1.05-0.90 (m,2H) ppm. LCMS (method A, ESI): RT=1.73 min, m/z=424.0 [M+H]⁺.

Example 23 Synthesis ofN-((1R,3R,5S)-8-((1r,4R)-4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

(Cpd. No. 539)

Step 1: Synthesis of5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 2-L 3-necked round-bottom flask was placed a solution ofN-((1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (20 g, 67.16 mmol, 1.00 equiv) in dichloromethane (800mL). Then DIEA (43 g, 332.71 mmol, 5.00 equiv) was added, followed bythe addition of 4-oxocyclohexane-1-sulfonyl chloride (14.45 g, 73.48mmol, 1.10 equiv) in portions over 5.5 hr (0.1 equiv for each portion).The resulting solution was stirred overnight at 20° C. The reactionmixture was washed with dilute hydrochloric acid (1N, 200 mL). Then theorganic phase was washed with NaHCO₃ (sat. 200 mL) and brine (sat. 200mL) respectively. The organic phase was dried over anhydrous Na₂SO₄ andconcentrated under vacuum. This resulted in 19 g (64%) of5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamideas a yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.14 (d, J=9 Hz, 1H), 6.34(s, 1H), 4.37-4.25 (m, 3H), 3.36-3.27 (m, 1H), 2.65-2.15 (m, 10H),2.13-1.9 (m, 7H), 1.20-1.10 (m, 2H), 1.05-0.95 (m, 2H) ppm. LCMS (methodC, ESI): RT=0.88 min, m/z=422.2 [M+H]⁺.

Step 2: Synthesis ofN-((1R,3R,5S)-8-(((1r,4R)-4-aminocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Into a 5-L round-bottom flask was placed a solution of5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(3 g, 7.12 mmol, 1.00 equiv) in methanol (3 L), then HCOONH₄ (17.6 g,279.12 mmol, 40.00 equiv) and acetic acid (852 mg, 14.19 mmol, 2.00equiv) were added. After stirred for 30 min at 25° C., NaBH₃CN (895 mg,14.24 mmol, 2.00 equiv) was added portion-wise. The resulting solutionwas stirred for 30 min at 25° C. The reaction mixture was concentratedunder vacuum. The resulting solid was extracted with ethyl acetate (100mL×5). The combined organic extracts were concentrated and the residuepurified by flash chromatography (DCE:MeOH=10:1). The crude product wasfurther purified by Prep-HPLC with the following conditions: Column, XBridge C18, 19*150 mm, 5 um; mobile phase, Mobile Phase A: Water/0.05%TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Detector, 254 nm. Thefractions containing product were combined and concentrated. They werethen treated with hydrochloric acid (12N, 1 mL) and concentrated againunder vacuum. This resulted in 1.0 g (31%) ofN-((1R,3R,5S)-8-((1r,4R)-4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride as a light yellow solid. ¹H-NMR (300 MHz, D₂O): δ 6.29 (s,1H), 4.21-4.00 (m, 3H), 3.28-3.10 (m, 2H), 2.30-2.05 (m, 7H), 2.05-1.87(m, 6H), 1.65-1.35 (m, 4H), 1.12-1.00 (m, 2H), 0.95-0.84 (m, 2H) ppm.LCMS (method D, ESI): RT=0.89 min, m/z=423.1 [M+H]⁺.

Example 24 Synthesis ofN-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (Cpd. No. 532)

Step 1: Synthesis of tert-butyl1-((1R,3r,5S)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)piperidin-4-ylcarbamate

Into a 250-mL round-bottom flask was placed tert-butylN-(piperidin-4-yl)carbamate (1.2 g, 5.99 mmol, 4.00 equiv),dichloromethane (20 mL), and DIEA (2.2 g, 17.02 mmol, 10.00 equiv).After stirring for 30 min,(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonylchloride (600 mg, 1.67 mmol, 1.00 equiv) was added at 0° C. Theresulting solution was stirred for 12 h at 20° C. The reaction mixturewas diluted by DCM (30 mL), and washed by water (10 mL×3). The organicextract was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnwith ethyl acetate/hexane (2:1). This resulted in 620 mg (71%) oftert-butyl1-((1R,3r,5S)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)piperidin-4-ylcarbamate.¹H-NMR (400 MHz, CDCl₃): δ 7.15 (d, J=7.2 Hz, 1H), 6.35 (s, 1H),4.50-4.45 (m, 1H), 4.36-4.28 (m, 1H), 4.20-4.10 (m, 2H), 3.75-3.50 (m,3H), 2.90-2.80 (m, 2H), 2.35-2.22 (m, 4H), 2.15-1.89 (m, 7H), 1.55-1.43(m, 11H), 1.18-1.12 (m, 2H), 1.04-0.96 (m, 2H) ppm. LCMS (method A,ESI): RT=1.45 min, m/z=546.0 [M+23]′.

Step 2: Synthesis ofN-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride

Into a 250-mL round-bottom flask was placed tert-butylN-[1-[(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]piperidin-4-yl]carbamate(600 mg, 1.15 mmol, 1.00 equiv) and dichloromethane (20 mL). Thenhydrogen chloride (gas) was introduced into mixture. The resultingsolution was stirred for 5 h at 20° C. The resulting mixture wasconcentrated under vacuum. The solids were collected by filtration. Thisresulted in 420 mg (87%) ofN-((1R,3r,5S)-8-(4-aminopiperidin-1-ylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride as a white solid. ¹H-NMR (300 MHz, D₂O): δ 6.31 (s, 1H),4.09 (s, 3H), 3.76 (d, J=9 Hz, 2H), 3.39-3.26 (m, 1H), 2.97-2.84 (m,2H), 2.30-1.90 (m, 11H), 1.74-1.56 (m, 2H), 1.15-1.02 (m, 2H), 0.96-0.86(m, 2H) ppm. LCMS (method B, ESI): RT=1.50 min, m/z=423.9 [M+H]⁺.

Example 25 Synthesis ofN-((1R,3r,5S)-8-(2,7-diazaspiro[3.5]nonan-2-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide2,2,2-trifluoroacetate (Cpd. No. 559)

Step 1: Synthesis of(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonylchloride

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed sulfuryl chloride (451 mg, 3.34mmol, 1.00 equiv). At −78° C., DIEA (870 mg, 6.73 mmol, 2.00 equiv) withN-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamidehydrochloride (1 g, 3.36 mmol, 1.00 equiv) in dichloromethane (50 mL)was added dropwise into the above solution at −78° C. (in a liquidnitrogen bath) in 5 min. The resulting solution was allowed to warm toroom temperature and stir overnight. The reaction mixture wasconcentrated under vacuum. The residue was dissolved in 40 ml of ethylacetate. The resulting mixture was washed with 50 mL of dilutedhydrochloric acid (1N). Then the mixture was dried over anhydrous sodiumsulfate and concentrated under vacuum. This resulted in 1 g (83%) of(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonylchloride as a white solid. ¹H-NMR (300 MHz, CD₃OD): δ 6.36 (s, 1H), 4.45(s, 2H), 4.17 (t, J=12 Hz, 1H), 2.50-2.02 (m, 9H), 1.17-1.09 (m, 2H),1.00-0.91 (m, 2H) ppm. LCMS (method A, ESI): RT=1.45 min, m/z=360.0[M+H]⁺.

Step 2: Synthesis of tert-butyl2-[(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate

Into a 50-mL round-bottom flask was placed tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate hydrochloride (876 mg, 3.33mmol, 4.14 equiv), DIEA (1.07 mg, 0.01 mmol, 0.01 equiv), anddichloromethane (5 mL). After the mixture was stirred for 30 min,(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonylchloride (290 mg, 0.81 mmol, 1.00 equiv) was added. The resultingsolution was stirred for 12 h at 20° C. The reaction mixture was dilutedwith 30 mL of dichloromethane and washed with water (10 mL×3). Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnwith ethyl acetate/hexane (2:1). This resulted in 355 mg (75%) oftert-butyl2-[(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylateas a white solid. ¹H-NMR (400 MHz, CDCl₃): δ 7.12 (d, 1H), 6.32 (s, 1H),4.35-4.15 (m, 3H), 3.60 (s, 4H), 3.35 (t, J=12 Hz, 4H), 2.35-1.85 (m,9H), 1.74 (t, J=12 Hz, 4H), 1.45 (s, 9H), 1.17-1.08 (m, 2H), 1.03-0.96(m, 2H) ppm. LCMS (method B, ESI): RT=1.52 min, m/z=450.2 [M-100]⁺.

Step 3: Synthesis of5-cyclopropyl-N-[(1R,3r,5S)-8-[2,7-diazaspiro[3.5]nonane-2-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamidetrifluoroacetate

Into a 25-mL round-bottom flask was placed tert-butyl2-[(1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]-2,7-diazaspiro[3.5]nonane-7-carboxylate(50 mg, 0.09 mmol, 1.00 equiv), dichloromethane (10 mL) andtrifluoroacetic acid (2.5 mL). The resulting solution was stirred for 4h at room temperature. The reaction mixture was concentrated undervacuum. The crude product was purified by Prep-HPLC with the followingconditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient:30% B to 70% B in 10 min; 254 nm. This resulted in 36.5 mg (83%) of5-cyclopropyl-N-[(1R,3r,5S)-8-[2,7-diazaspiro[3.5]nonane-2-sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamidetrifluoroacetate as a solid. ¹H-NMR (300 MHz, D₂O): δ 6.28 (s, 1H), 4.08(s, 3H), 3.66 (s, 4H), 3.15-3.05 (m, 4H), 2.24-1.86 (m, 13H), 1.08-099(m, 2H), 0.92-0.84 (m, 2H) ppm. LCMS (method B, ESI): RT=1.67 min,m/z=450.0 [M+H]⁺.

Example 26 Synthesis of5-ethyl-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(Cpd. No. 562)

Step 1: Synthesis of ethyl 5-ethylisoxazole-3-carboxylate

Into a 250-mL round-bottom flask was placed ethyl 2,4-dioxohexanoate (10g, 69.36 mmol, 1.00 equiv), ethanol (100 mL), and NH₂OH—HCl (4.95 g,70.23 mmol, 1.2 equiv). The resulting solution was stirred for 16 hoursat 80° C. in an oil bath. The reaction mixture was concentrated undervacuum and the residue dissolved in 50 mL of ethyl acetate. Theresulting mixture was washed with 2×20 mL of water. The organic phasewas dried and concentrated under vacuum. This resulted in 10 g (46%) ofethyl 5-ethyl-1,2-oxazole-3-carboxylate as a yellow solid. LCMS (methodA, ESI): RT=1.37 min, m/z=170.0 [M+H]⁺.

Step 2: Synthesis of 5-ethylisoxazole-3-carboxylic acid

Into a 250-mL round-bottom flask was placed ethyl5-ethyl-1,2-oxazole-3-carboxylate (5 g, 29.55 mmol, 1.00 equiv), ethanol(50 mL), and sodium hydroxide (2.4 g, 60.00 mmol, 2.03 equiv). This wasfollowed by the addition of water (8 mL) dropwise with stirring over 10mins. The resulting solution was stirred for 16 hours at 25° C. The pHvalue of the solution was adjusted to 4 with hydrochloric acid (6N). Theresulting solution was extracted with 50 mL of dichloromethane. Theresulting mixture was concentrated under vacuum. This resulted in 3 g(72%) of 5-ethyl-1,2-oxazole-3-carboxylic acid as a yellow solid. ¹H-NMR(300 MHz, DMSO): δ13.8 (s, 1H), 6.58 (s, 1H), 2.85 (q, J₁=7.5 Hz, 2H),1.32 (t, J=7.5 Hz, 3H) ppm. LCMS (method C, ESI): RT=2.60 min,m/z=142.0411.0 [M+H]⁺.

Step 3: Synthesis of (1R,3r,5S)-tert-butyl3-(5-ethylisoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate

Into a 50-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.33 mmol, 1.00equiv), dichloromethane (13 mL), 5-ethyl-1,2-oxazole-3-carboxylic acid(480 mg, 3.40 mmol, 1.10 equiv), 1-hydroxybenzotrizole (431 mg, 3.19mmol, 1.50 equiv), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (1.2 g, 6.26 mmol, 3.00 equiv) and triethylamine (860 mg,8.50 mmol, 4.00 equiv). The resulting solution was stirred for 16 h at25° C. The reaction mixture was washed with 2×30 mL of H₂O. The waterlayers were back extracted with 2×30 mL of dichloromethane and theorganic layers combined and concentrated under vacuum. The residue waschromatographed on a silica gel column with ethyl acetate/petroleumether (6:1). This resulted in 350 mg (76%) of (1R,3r,5S)-tert-butyl3-(5-ethylisoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylateasa yellow solid. LCMS (method C, ESI): RT=0.93 min, m/z=350.0 [M+H]⁺.

Step 4: Synthesis ofN-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-ethylisoxazole-3-carboxamide

Into a 50-mL round-bottom flask was placed (1R,3r,5S)-tert-butyl3-(5-ethylisoxazole-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate(350 mg, 1.00 mmol, 1.00 equiv) and dichloromethane (30 mL). To theabove hydrogen chloride (gas) was introduced. The resulting solution wasstirred for 2 h at 25° C. The reaction mixture was concentrated undervacuum. This resulted in 300 mg (HCl salt) ofN-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-oxazole-3-carboxamideas a white solid. LCMS (method A, ESI): RT=0.97 min, m/z=250.0 [M+H]⁺.

Step 5: Synthesis of benzyl4-(((1R,3r,5S)-3-(5-ethylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placedN-[(1R,3r,5S)-8-azabicyclo[3.2.1]octan-3-yl]-5-ethyl-1,2-oxazole-3-carboxamide(100 mg, 0.40 mmol, 1.00 equiv), and tetrahydrofuran (5 mL). This wasfollowed by the addition of lithium bis(trimethylsilyl)amide (1N in THF,1.5 mL) dropwise with stirring at −70° C. To this was added benzyl4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (200 mg, 0.60 mmol,1.50 equiv) in several portions at −70° C. The resulting solution wasstirred for 30 min at −70° C. in a dry ice bath. The reaction mixturewas stirred for an additional 16 h at 25° C. The resulting solution wasdiluted with 30 mL of ethyl acetate and washed with 2×15 mL of H₂O. Theresulting mixture was concentrated under vacuum. The residue waschromatographed on a silica gel column with ethyl acetate/petroleumether (2:3). This resulted in 140 mg (64%) of benzyl4-[[(1R,3r,5S)-3-(5-ethyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylateas white solid. LCMS (method C, ESI): RT=1.53 min, m/z=545.0 [M+H]⁺.

Step 6: Synthesis of5-ethyl-N-((1R,3r,5S)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 50-mL round-bottom flask was placed benzyl4-[[(1R,3r,5S)-3-(5-ethyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-sulfonyl]methyl]piperidine-1-carboxylate(120 mg, 0.22 mmol, 1.00 equiv) and hydrochloric acid (12N, 20 mL). Theresulting solution was stirred for 2 h at 25° C. The reaction mixturewas concentrated under vacuum. The crude product (120 mg) was purifiedby Prep-HPLC with the following conditions (Prep-HPLC-025): Column,XBridge Prep Phenyl OBD Column, 5 um, 19*150 mm; mobile phase, Waterwith 10 mmol NH₄HCO₃ and MeCN (20.0% MeCN up to 75.0% in 10 min, up to95.0% in 1 min, hold 95.0% in 1 min, down to 20.0% in 2 min); Detector,UV 254/220 nm. This resulted in 34.8 mg (38%) of5-ethyl-N-[(1R,3r,5S)-8-[(piperidin-4-ylmethane)sulfonyl]-8-azabicyclo[3.2.1]octan-3-yl]-1,2-oxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 6.47 (s, 1H), 4.26 (d,J=23.0 Hz, 2H), 4.16 (d, J=6.4 Hz, 1H), 3.14-3.06 (m, 4H), 2.89 (q,J₁=7.6 Hz, J₂ ⁼15.2 Hz, 2H), 2.76 (q, J₁=10.8 Hz, J₂=12.8 Hz, 2H),2.32-2.26 (m, 2H), 2.10-1.91 (m, 9H), 1.44-1.38 (m, 5H) ppm. LCMS(method C, ESI): RT=2.60 min, m/z=411.0 [M+H]⁺.

Example 27 Synthesis ofN-((1R,3r,5S)-8-((1s,4S)-4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (Cpd. No. 540)

Into a 5-L round-bottom flask was placed a solution of5-cyclopropyl-N-((1R,3r,5S)-8-((4-oxocyclohexyl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(3 g, 7.12 mmol, 1.00 equiv) in methanol (3 L). Then HCOONH₄ (17.6 g,279.12 mmol, 40.00 equiv) and acetic acid (852 mg, 14.19 mmol, 2.00equiv) were added. After stirring for 30 min at 25° C., NaBH₃CN (895 mg,14.24 mmol, 2.00 equiv) was added. The resulting solution was stirredfor 30 min at 25° C. The reaction mixture was concentrated under vacuum.The resulting solid was extracted with ethyl acetate (100 mL×5). Thecombined organic layers were concentrated and the residue purified byflash chromatography (DCE:MeOH=10:1). The product was further purifiedby Prep-HPLC with the following conditions: Column, X Bridge C18, 19*150mm, 5 um; mobile phase, Mobile Phase A:Water/0.05% TFA, Mobile Phase B:ACN; Flow rate: 20 mL/min; Detector, 254 nm. The fractions containingproduct were combined and concentrated, then acidified with hydrochloricacid (12N, 0.5 mL), and concentrated again under vacuum. This resultedin 200 mg ofN-((1R,3R,5S)-8-((1s,4S)-4-aminocyclohexylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride as a light yellow solid. ¹H-NMR (300 MHz, D₂O): δ 6.25 (s,1H), 4.15 (s, 2H), 4.10-4.00 (m, 1H), 3.42-3.25 (m, 2H), 2.25-1.75 (m,17H), 1.09-1.00 (m, 2H), 0.92-0.81 (m, 2H) ppm. LCMS (method A, ESI):RT=1.69 min, m/z=445.2 [M+23]′.

Example 28 Synthesis ofN-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide(Cpd. No. 766)

Step 1: Synthesis ofN-((1R,3r,5S)-8-(4-bromophenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placedN-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (500 mg, 1.68 mmol, 1.00 equiv), and dichloromethane (10mL). This was followed by the dropwise addition of TEA (510 mg, 5.04mmol, 3.00 equiv) with stirring at 0° C. To this was added4-bromobenzene-1-sulfonyl chloride (470 mg, 1.84 mmol, 1.10 equiv) inseveral batches at 0° C. The resulting solution was stirred overnight atroom temperature. The reaction mixture was diluted with 10 mL ofdichloromethane. The resulting mixture was washed with 3×5 mL of H₂O.The organic phase was collected and concentrated under vacuum. Theresidue was chromatographed on a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 742 mg (92%) ofN-((1R,3r,5S)-8-(4-bromophenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.78-7.70 (m, 2H),7.69-7.60 (m, 2H), 7.04 (br, 1H), 6.30 (s, 1H), 4.28 (brs, 3H),2.39-2.25 (m, 2H), 2.11-2.00 (m, 1H), 1.97-1.72 (m, 6H), 1.18-1.07 (m,2H), 1.00-0.92 (m, 2H) ppm. LCMS (Method D, ESI): RT=1.57 min, m/z=480.0[M+H]⁺.

Step 2: Synthesis of5-cyclopropyl-N-((1R,3r,5S)-8-(4-(prop-1-en-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placedN-((1R,3r,5S)-8-(4-bromophenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide(642 mg, 1.34 mmol, 1.00 equiv),4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (293 mg, 1.74mmol, 1.30 equiv), Pd(dppf)Cl₂ (98 mg, 0.13 mmol, 0.10 equiv), potassiumcarbonate (555 mg, 4.02 mmol, 3.00 equiv), 1,4-dioxane (15 mL) and water(1.5 mL). The resulting solution was stirred for 14 h at 90° C. Thereaction mixture was concentrated under vacuum. The resulting solutionwas diluted with 25 mL of H₂O and extracted with 3×10 mL of ethylacetate. The organic layers were combined and dried over anhydroussodium sulfate. The residue was chromatographed on a silica gel columnwith ethyl acetate/petroleum ether (1:2). This resulted in 544 mg (92%)of5-cyclopropyl-N-((1R,3r,5S)-8-(4-(prop-1-en-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamideas a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.82 (d, J=8.7 Hz, 2H),7.56 (d, J=8.7 Hz, 2H), 7.05 (br, 1H), 6.30 (s, 1H), 5.48 (s, 1H), 5.24(s, 1H), 4.29 (brs, 3H), 2.41-2.26 (m, 2H), 2.17 (s, 3H), 2.11-2.00 (m,1H), 1.97-1.70 (m, 6H), 1.16-1.05 (m, 2H), 1.01-0.92 (m, 2H) ppm. LCMS(Method D, ESI): RT=1.59 min, m/z=442.0 [M+H]⁺.

Step 3: Synthesis ofN-((1R,3r,5S)-8-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 100-mL round-bottom flask was placed5-cyclopropyl-N-((1R,3r,5S)-8-(4-(prop-1-en-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(544 mg, 1.23 mmol, 1.00 equiv), AcOH (39 mL), 2-chloroacetonitrile(1.85 g, 24.50 mmol, 19.89 equiv). This was followed by the dropwiseaddition of sulfuric acid (98%, 9.7 mL) with stirring at 0° C. Theresulting solution was stirred for 14 h at 25° C. The reaction mixturewas diluted with 100 mL of ice-water. The pH of the solution wasadjusted to 7 with sodium carbonate (sat. aq.). The resulting solutionwas extracted with 3×50 ml, of ethyl acetate and the organic layerscombined and dried over anhydrous sodium sulfate. After concentration,the residue was chromatographed on a silica gel column with ethylacetate/petroleum ether (1:1). This resulted in 505 mg (77%) ofN-((1R,3r,5S)-8-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.83 (d, J=8.7 Hz, 2H),7.48 (d, J=8.4 Hz, 2H), 7.05 (br, 1H), 6.85 (brs, 1H), 6.30 (s, 1H),4.27 (brs, 3H), 3.98 (s, 2H), 2.40-2.26 (m, 2H), 2.11-2.00 (m, 1H),1.95-1.76 (m, 6H), 1.75 (s, 6H), 1.15-1.05 (m, 2H), 1.00-0.91 (m, 2H)ppm. LCMS (Method D, ESI): RT=1.07 min, m/z=535.0 [M+H]⁺.

Step 4: Synthesis ofN-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide

Into a 25-mL round-bottom flask was placedN-((1R,3r,5S)-8-(4-(2-(2-chloroacetamido)propan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide(593 mg, 1.11 mmol, 1.00 equiv), ethanol (6.0 mL), and thiourea (101 mg,1.33 mmol, 1.20 equiv). This was followed by the dropwise addition ofAcOH (1.2 mL) with stirring. The resulting solution was stirred for 12 hat 85° C. The reaction mixture was concentrated under vacuum. Theresidue was dissolved in 10 mL of ethyl acetate and washed with 2×5 mLof H₂O. Concentration yielded 465 mg (91%) ofN-((1S,3r,5R)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas an off-white solid. The crude product (100 mg) was purified byPrep-HPLC with the following conditions: Column: X Bridge C18, 19*150mm, 5 um; Mobile Phase A: Water/10 mmol/L NH₄HCO₃, Mobile Phase B: MeOH;Flow rate: 30 mL/min; Gradient: 45% B to 75% B in 06 min; 254 nm. 120 mLof fractions contained product was obtained resulting in 18.4 mg ofN-((1R,3r,5S)-8-(4-(2-aminopropan-2-yl)phenylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamideas a white solid. ¹H-NMR (400 MHz, CD₃OD): δ 7.87 (d, J=8.8 Hz, 2H),7.73 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.27 (brs, 2H), 4.20-4.10 (m, 1H),2.32-2.21 (m, 2H), 2.20-2.10 (m, 1H), 2.00 (d, J=14.4 Hz, 2H), 1.93-1.82(m, 2H), 1.63-1.55 (m, 2H), 1.54 (s, 6H), 1.18-1.10 (m, 2H), 1.00-0.91(m, 2H) ppm. LCMS (Method A, ESI): RT=1.77 min, m/z=481.0 [M+Na]⁺.

Example 29 Synthesis of5-cyclopropyl-N-((1S,3r,5R)-8-((l-methylpiperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide(Cpd. No. 770)

Step 1: Synthesis of benzyl4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate

Into a 1000-mL round-bottom flask, was placed benzyl4-(hydroxymethyl)piperidine-1-carboxylate (100 g, 401.11 mmol, 1.00equiv), dichloromethane (300 mL), triethylamine (121 g, 1.20 mol, 3.00equiv). This was followed by the addition of methanesulfonyl chloride(91.6 g, 799.64 mmol, 2.00 equiv) dropwise with stirring at 0° C. Theresulting solution was stirred for 16 h at 25° C. The resulting mixturewas washed with 2×500 mL of H₂O. The resulting mixture was concentratedunder vacuum. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:2). This resulted in 116 g (88%) ofbenzyl 4-((methylsulfonyloxy)methyl)piperidine-1-carboxylate as a yellowsolid. ¹H-NMR (300 MHz, CDCl₃): δ 7.40-7.29 (m, 5H), 5.07 (s, 2H),4.08-4.01 (m, 4H), 3.17 (s, 3H), 2.90-2.70 (m, 2H), 1.99-1.86 (m, 1H),1.69-1.66 (m, 2H), 1.20-1.15 (m, 2H) ppm. LCMS (method D, ESI): RT=1.46min, m/z=328.0 [M+H]⁺.

Step 2: Synthesis of benzyl 4-(acetylthiomethyl)piperidine-1-carboxylate

Into a 2000-mL round-bottom flask, was placed benzyl4-[(methanesulfonyloxy)methyl]piperidine-1-carboxylate (116 g, 354.31mmol, 1.00 equiv), acetonitrile (1000 mL),1-(potassiosulfanyl)ethan-1-one (190 g, 1.66 mol, 5.00 equiv). Theresulting solution was stirred for 2 h at 80° C. in an oil bath. Theresulting solution was extracted with 2×500 mL of ethyl acetate and theorganic layers combined and dried over anhydrous sodium sulfate andconcentrated under vacuum. This resulted in 105 g (96%) of benzyl4-(acetylthiomethyl)piperidine-1-carboxylate as red oil. ¹H-NMR (300MHz, CDCl₃): δ 7.40-7.29 (m, 5H), 5.12 (s, 2H), 4.20-4.13 (m, 2H),2.83-2.70 (m, 4H), 2.34 (s, 3H), 1.78-1.70 (m, 2H), 1.68-1.57 (m, 1H),1.28-1.22 (m, 2H) ppm. LCMS (method A, ESI): RT=1.53 min, m/z=308.0[M+H]⁺

Step 3: Synthesis of benzyl4-(chlorosulfonylmethyl)piperidine-1-carboxylate

Into a 1000-mL round-bottom flask, was placed benzyl4-[(acetylsulfanyl)methyl]piperidine-1-carboxylate (105 g, 341.57 mmol,1.00 equiv), acetic acid (500 mL), water (250 mL). This was followed bythe addition of N-chlorosuccinimide (160 g, 1.20 mol, 3.50 equiv) inseveral batches at 0° C. The resulting solution was stirred for 2 h at25° C. The resulting solution was extracted with 2×500 mL ofdichloromethane and the organic layers combined and concentrated undervacuum. The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:4). This resulted in 95 g (84%) of benzyl4-(chlorosulfonylmethyl)piperidine-1-carboxylate as a light yellowsolid. ¹H-NMR (300 MHz, CDCl₃): δ 7.41-7.28 (m, 5H), 5.12 (s, 2H),4.24-4.08 (m, 2H), 3.65 (d, J=6.3 Hz, 2H), 2.89-2.73 (m, 3H), 2.43-2.31(m, 1H), 2.07-1.95 (m, 2H), 1.43-1.21 (m, 2H) ppm. LCMS (method A, ESI):RT=1.48 min, m/z=332.0 [M+H]⁺.

Step 4: Synthesis of benzyl4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate

Into a 1000-mL round-bottom flask, was placedN-((1S,3r,5R)-8-aza-bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamidehydrochloride (28.4 g, 95.37 mmol, 1.00 equiv), dichloromethane (500mL), triethylamine (100 g, 988.24 mmol, 10.00 equiv). This was followedby the addition of benzyl4-[(chlorosulfonyl)methyl]piperidine-1-carboxylate (35 g, 105.48 mmol,1.10 equiv) in several batches at −70° C. The resulting solution wasstirred for 16 h at 25° C. The resulting mixture was washed with 2×300mL of H₂O. The organic phase was collected. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (1:1). This resulted in 34 g(64%) of benzyl4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylateas a white solid. ¹H-NMR (300 MHz, CDCl₃): δ 7.36-7.26 (m, 5H), 7.10 (d,J=7.2 Hz, 1H), 6.32 (s, 1H), 5.12 (s, 2H), 4.31-4.16 (m, 5H), 2.92-2.84(m, 4H), 2.31-1.92 (m, 12H), 1.31-1.24 (m, 2H), 1.14-1.09 (m, 2H),1.01-0.97 (m, 2H) ppm. LCMS (method B, ESI): RT=1.59 min,m/z=557.0[M+H]⁺.

Step 5: Synthesis of5-cyclopropyl-N-((1S,3r,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamidehydrochloride

Into a 1000-mL round-bottom flask, was placed benzyl4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3-carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate(48 g, 86.23 mmol, 1.00 equiv), hydrochloric acid (12 N, 500 mL). Theresulting solution was stirred for 8 h at 25° C. The resulting mixturewas concentrated under vacuum. This resulted in 39 g (99%) of5-cyclopropyl-N-((1S,3r,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamidehydrochloride as an off-white solid. LCMS (method A, ESI): RT=0.99 min,m/z=423.0[M+H]⁺

Step 6: Synthesis of5-cyclopropyl-N-((1S,3r,5R)-8-((l-methylpiperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

In Into a 2000-mL round-bottom flask, was placed5-cyclopropyl-N-((1S,3r,5R)-8-(piperidin-4-ylmethylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamidehydrochloride (42 g, 91.50 mmol, 1.00 equiv), methanol (800 mL),formaldehyde (40 mL), acetic acid (8 mL). The resulting solution wasstirred for 0.5 h at 25° C. This was followed by the addition of sodiumcyanoborohydride (11 g, 175.05 mmol, 2.00 equiv) in several batches at0° C. The resulting solution was stirred for 2 h at 25° C. The resultingmixture was concentrated under vacuum. The pH value of the solution wasadjusted to 10 with sodium hydroxide (1 N). The resulting solution wasextracted with 2×500 mL of dichloromethane and the organic layerscombined and dried over anhydrous sodium sulfate. The resulting mixturewas concentrated under vacuum. This resulted in 38.9 g (98%) of5-cyclopropyl-N-((1S,3r,5R)-8-((1-methylpiperidin-4-yl)methylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamideas an off-white solid. ¹H-NMR (300 MHz, CD₃OD): δ 6.41 (s, 1H),4.28-4.18 (m, 3H), 3.10 (d, J=6.0 Hz, 2H), 2.94 (d, J=12.0 Hz, 2H),2.34-1.95 (m, 17H), 1.60-1.40 (m, 2H), 1.21-1.15 (m, 2H), 1.05-0.98 (m,2H) ppm. LCMS (method B, ESI): RT=1.64 min, m/z=437.1 [M+H]⁺.

Example 30 SMYD3 Biochemical Assay General Materials

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), Tris, Tween20,dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), andTris(2-carboxyethyl)phosphine hydrochloride solution (TCEP) werepurchased from Sigma-Aldrich at the highest level of purity possible.³H-SAM was purchase from American Radiolabeled Chemicals with a specificactivity of 80 Ci/mmol. 384-well opaque white OptiPlates and SPA beads(Perkin Elmer, catalog # RPNQ0013) were purchased from PerkinElmer.

Substrates

N-terminally GST-tagged MEKK2 (MAP3K2) protein corresponding toreference sequence AAF63496.3 was purchased from Life Technologies(catalog # PV4010). This protein was expressed in High Five insect cellsand purified to >85% purity. Protein identity was confirmed by MS/MSanalysis after proteolytic digestion. The protein sequence used was:

(SEQ ID No. 1). MAPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLVPRHNQTSLYKKAGTMDDQQALNSIMQDLAVLHKASRPALSLQETRKAKSSSPKKQNDVRVKFEHRGEKRILQFPRPVKLEDLRSKAKIAFGQSMDLHYTNNELVIPLTTQDDLDKALELLDRSIHMKSLKILLVINGSTQATNLEPLPSLEDLDNTVFGAERKKRLSIIGPTSRDRSSPPPGYIPDELHQVARNGSFTSINSEGEFIPESMEQMLDPLSLSSPENSGSGSCPSLDSPLDGESYPKSRMPRAQSYPDNHQEFSDYDNPIFEKFGKGGTYPRRYHVSYHHQEYNDGRKTFPRARRTQGNQLTSPVSFSPTDHSLSTSSGSSIFTPEYDDSRIRRRGSDIDNPTLTVMDISPPSRSPRAPTNWRLGKLLGQGAFGRVYLCYDVDTGRELAVKQVQFDPDSPETSKEVNALECEIQLLKNLLHERIVQYYGCLRDPQEKTLSIFMEYMPGGSIKDQLKAYGALTENVTRKYTRQILEGVHYLHSNMIVHRDIKGANILRDSTGNVKLGDFGASKRLQTICLSGTGMKSVTGTPYWMSPEVISGQGYGRKADIWSVACTVVEMLTEKPPWAEFEAMAAIFKIATQPTNPKLPPHVSDYTRDFLKRIFVEAKLRPSADELLRHMFVHYH.

Molecular Biology

Full-length human SMYD3 isoform 1 (BAB86333) was inserted into amodified pET21b plasmid containing a His6 tag and TEV and SUMO cleavagesites. Because two common variants of SMYD3 exist in the population,site directed mutagenesis was subsequently performed to change aminoacid 13 from an asparagine to a lysine, resulting in plasmid pEPZ533. Alysine at position 13 conforms to the more commonly occurring sequence(NP 001161212).

Protein Expression

E. coli (BL21 codonplus RIL strain, Stratagene) were transformed withplasmid pEPZ553 by mixing competent cells and plasmid DNA and incubatingon ice for 30 minutes followed by heat shock at 42° C. for 1 minute andcooling on ice for 2 minutes. Transformed cells were grown and selectedon LB agar with 100 μg/mL ampicillin and 17 μg/mL chloramphenicol at 37°C. overnight. A single clone was used to inoculate 200 mL of LB mediumwith 100 μg/mL ampicillin and 17 μg/mL chloramphenicol and incubated at37° C. on an orbital shaker at 180 rpm. Once in log growth, the culturewas diluted 1:100 into 2 L of LB medium and grown until OD₆₀₀ was about0.3 after which the culture was incubated at 15° C. and 160 rpm. OnceOD₆₀₀ reached about 0.4, IPTG was added to a final concentration of 0.1mM and the cells were grown overnight at 15° C. and 160 rpm. Cells wereharvested by centrifugation at 8000 rpm, for 4 minutes at 4° C. andstored at −80° C. for purification.

Protein Purification

Expressed full-length human His-tagged SMYD3 protein was purified fromcell paste by Nickel affinity chromatography after equilibration of theresin with Buffer A (25 mM Tris, 200 mM NaCl, 5% glycerol, 5 mMβ-mercaptoethanol, pH7.8). The column was washed with Buffer B (Buffer Aplus 20 mM imidazole) and His-tagged SMYD3 was eluted with Buffer C(Buffer A plus 300 mM imidazole). The His tag, TEV and SUMO cleavagesites were removed generating native SMYD3 by addition of ULP1 proteinat a ratio of 1:200 (ULP1:SMYD3). Imidazole was removed by dialysisovernight in Buffer A. The dialyzed solution was applied to a secondNickel column and the native SMYD3 protein was collected from the columnflow-through. The flow-through was dialyzed in Buffer D (25 mM Tris, 5%glycerol, 5 mM β-mercaptoethanol, 50 mM NaCl, pH7.8) and ULP1 wasremoved using a Q sepharose fast flow column. SMYD3 was eluted in BufferA and further purified using an S200 size-exclusion column equilibratedwith Buffer A. SMYD3 was concentrated to 2 mg/mL with a final purity of89%.

Predicted Translation:

SMYD3 (Q9H7B4) (SEQ ID No. 2).MEPLKVEKFATAKRGNGLRAVTPLRPGELLFRSDPLAYTVCKGSRGVVCDRCLLGKEKLMRCSQCRVAKYCSAKCQKKAWPDHKRECKCLKSCKPRYPPDSVRLLGRVVFKLMDGAPSESEKLYSFYDLESNINKLTEDKKEGLRQLVMTFQHFMREEIQDASQLPPAFDLFEAFAKVICNSFTICNAEMQEVGVGLYPSISLLNHSCDPNCSIVFNGPHLLLRAVRDIEVGEELTICYLDMLMTSEERRKQLRDQYCFECDCFRCQTQDKDADMLTGDEQVWKEVQESLKKIEELKAHWKWEQVLAMCQAIISSNSERLPDINIYQLKVLDCAMDACINLGLLEEALFYGTRTMEPYRIFFPGSHPVRGVQVMKVGKLQLHQGMFPQAMKNLRLAFDIMRVTHGREHSLIEDLILLLEECDANIRAS. 

General Procedure for SMYD3 Enzyme Assays on MEKK2 Protein Substrate

The assays were all performed in a buffer consisting of 25 mM Tris-Cl pH8.0, 1 mM TCEP, 0.005% BSG, and 0.005% Tween 20, prepared on the day ofuse. Compounds in 100% DMSO (1 ul) were spotted into a 384-well whiteopaque OptiPlate using a Bravo automated liquid handling platformoutfitted with a 384-channel head (Agilent Technologies). DMSO (1 ul)was added to Columns 11, 12, 23, 24, rows A-H for the maximum signalcontrol and 1 ul of SAH, a known product and inhibitor of SMYD3, wasadded to columns 11, 12, 23, 24, rows I-P for the minimum signalcontrol. A cocktail (40 ul) containing the SMYD3 enzyme was added byMultidrop Combi (Thermo-Fisher). The compounds were allowed to incubatewith SMYD3 for 30 min at room temperature, then a cocktail (10 ul)containing SAM and MEKK2 was added to initiate the reaction (finalvolume=51 ul). The final concentrations of the components were asfollows: SMYD3 was 0.4 nM, ³H-SAM was 8 nM, MEKK2 was 12 nM, SAH in theminimum signal control wells was 1 mM, and the DMSO concentration was2%. The assays were stopped by the addition of non-radiolabeled SAM (10ul) to a final concentration of 100 uM, which dilutes the ³H-SAM to alevel where its incorporation into MEKK2 is no longer detectable.Radiolabeled MEKK2 was detected using a scintillation proximity assay(SPA). 10 uL of a 10 mg/mL solution of SPA beads in 0.5 M citric acidwas added and the plates centrifuged at 600 rpm for 1 min to precipitatethe radiolabeled MEKK2 onto the SPA beads. The plates were then read ina PerkinElmer TopCount plate reader to measure the quantity of³H-labeled MEKK2 as disintegrations per minute (dpm) or alternatively,referred to as counts per minute (cpm).

% Inhibition Calculation

${\% \mspace{14mu} {inh}} = {100 - {\left( \frac{{dpm}_{cmpd} - {dpm}_{\min}}{{dpm}_{\max} - {dpm}_{\min}} \right) \times 100}}$

Where dpm=disintegrations per minute, cmpd=signal in assay well, and minand max are the respective minimum and maximum signal controls.

Four-Parameter IC50 Fit

$Y = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + \left( \frac{X}{{IC}_{50}} \right)^{{HIll}\mspace{14mu} {Coefficient}}} \right.}}$

Where top and bottom are the normally allowed to float, but may be fixedat 100 or 0 respectively in a 3-parameter fit. The Hill Coefficientnormally allowed to float but may also be fixed at 1 in a 3-parameterfit. Y is the % inhibition and X is the compound concentration.

SMYD3 biochemical assay data for representative Compounds of theDisclosure are presented in Tables 1A, 2A, and 3A in the column titled“SMYD3 Biochem IC₅₀ (μM).”

Example 31 SMYD3 Cell Assay Trimethyl-MEKK2-in-Cell Western Assay

293T/17 adherent cells were purchased from ATCC (American Type CultureCollection), Manassas, Va., USA. MEM/Glutamax medium, Optimem ReducedSerum medium, penicillin-streptomycin, 0.05% trypsin and 1×D-PBS werepurchased from Life Technologies, Grand Island, N.Y., USA. PBS-10× waspurchased from Ambion, Life Technologies, Grand Island, N.Y., USA. PBSwith Tween 20 (PBST (10×)) was purchased from KPL, Gaithersburg, Md.,USA. Tet System FBS-approved FBS US Source was purchased from Clontech,Mountain View, Calif., USA. Odyssey blocking buffer, 800CW goatanti-rabbit IgG (H+L) antibody, 680CW Goat anti-mouse IgG (H+L) andLicor Odyssey infrared scanner were purchased from Licor Biosciences,Lincoln, Nebr., USA. Tri-methyl-Lysine [A260]-MEKK2 antibody, MEKK2 andSMYD3 plasmids were made at Epizyme. Anti-flag monoclonal mouse antibodywas purchased from Sigma, St. Louis, Mo., USA. Methanol was purchasedfrom VWR, Franklin, Mass., USA. 10% Tween 20 was purchased from KPL,Inc., Gaithersburg, Md., USA. Fugene was purchased from Promega,Madison, Wis., USA. The Biotek ELx405 was purchased from BioTek,Winooski, Vt., USA. The multidrop combi was purchased from ThermoScientific, Waltham, Mass., USA.

293T/17 adherent cells were maintained in growth medium (MEM/Glutamaxmedium supplemented with 10% v/v Tet System FBS and cultured at 37° C.under 5% CO₂.

Cell Treatment, in Cell Western (ICW) for Detection ofTrimethyl-Lysine-MEKK2 and MEKK2.

293T/17 cells were seeded in assay medium at a concentration of 33,333cells per cm² in 30 mL medium per T150 flask and incubated at 37° C.under 5% CO₂. Plasmids were prepared for delivery to cells by firstmixing 1350 μL Opti-MEM with Fugene (81 μL) in a sterile Eppendorf andincubated for five minutes at room temperature (RT). MEKK2-flag (13.6ug/T150) MEKK2 p3XFlag-CMV-14 with C-3XFlag and SMYD3 (0.151 ug/T150)SMYD3 p3XFlag-CMV-14 without C-3XFlag plasmids were aliquotted to a 1.7mL sterile microfuge tube. The gene ID for MEKK2 and SMYD3 is NM006609.3 and Q9H7B4, respectively. Entire volume of Opti-MEM/Fugenemixture was then added to a microfuge tube containing DNA plasmid, mixedand then incubated×15 minutes at RT. The medium on the 293T/17 cells wasrefreshed, and the DNA/Fugene complex is added aseptically to eachflask, rocked gently, and incubated at 37 C for 5 hours. Medium was thenremoved, and cells were washed once with PBS in the flask. Trypsin 0.05%(3 mL) was added and cells incubated for three minutes. Room temperatureMEM+10% Tet system FBS was added and cells were mixed gently, andcounted using the Vi-cell. Cells were seeded at 100,000 cells/mL in 50μL MEM/10% Tet FBS/Pen/Strep to a 384 well black/clear poly-D-lysinecoated plate containing test agent diluted in DMSO. The final topconcentration of test compound was 40 μM. The total concentration ofDMSO did not exceed 0.2% (v/v). Plates were incubated×30 minutes at RTin low-airflow area, followed by incubation at 37° C. under 5% CO₂ for24 hours. Medium was aspirated from all wells of assay plates prior tofixation and permeabilization with ice cold (−20° C.) methanol (90μL/well) for ten minutes. Plates were rinsed with PBS three times onBioTek ELx405. PBS was removed with a final aspiration, and Odysseyblocking buffer (50 μL/well) was added to each well and incubated forone hour at RT. Primary antibody solution was prepared(anti-trimethyl-MEKK2 at 1:600 dilution plus mouse anti-flag antibody at1:10,000 dilution in diluent (Odyssey Blocking buffer+0.1% Tween 20))and 20 μL per well was dispensed using the Multidrop Combi. Assay plateswere then sealed with foil, and incubated overnight at 4° C. Plates werewashed five times with PBS-Tween (1×) on Biotek ELx405 and blotted onpaper towel to remove excess reagent. Detection antibody solution (IRDye800 CW goat anti-rabbit IgG diluted 1:400 in diluent (Odyssey Blockingbuffer+0.1% Tween 20), plus IRDye 680CW goat anti-mouse IgG at 1:500 indiluent (Odyssey Blocking buffer+0.1% Tween 20) was added (20 μL/well)and incubated in dark for one hour at RT. Plates were then washed fourtimes with PBS-T (1×) on ELx405. A final rinse with water was performed(115 μL/well×three washes on the ELx405). Plates were then centrifugedupside down, on paper towel, at 200×g to remove excess reagent. Plateswere left to dry in dark for one hour. The Odyssey Imager was used tomeasure the integrated intensity of 700 and 800 wavelengths atresolution of 84 μm, medium quality, focus offset 4.0, 700 channelintensity=3.5 to measure the MEKK2-flag signal, 800 channel intensity=5to measure the Trimethyl-MEKK2 signal of each well.

Calculations:

First, the ratio for each well was determined by:

$\left( \frac{{Trimethyl}\mspace{14mu} {MEKK}\; 2\mspace{14mu} 800\mspace{14mu} {nm}\mspace{14mu} {value}}{{flag}\mspace{14mu} {tagged}\mspace{14mu} {MEKK}\; 2\mspace{14mu} 700\mspace{11mu} {nm}\mspace{14mu} {value}} \right)$

Each plate included fourteen control wells of DMSO only treatment(Minimum Inhibition) as well as fourteen control wells for maximuminhibition (Background). The average of the ratio values for eachcontrol type was calculated and used to determine the percent inhibitionfor each test well in the plate. Reference compound was serially dilutedtwo-fold in DMSO for a total of nine test concentrations, beginning at40 μM.

Percent inhibition was calculated (below).

${{Percent}\mspace{14mu} {Inhibition}} = {100 - \left( {\left( \frac{\begin{matrix}{\left( {{Individual}\mspace{14mu} {Test}\mspace{14mu} {Sample}\mspace{14mu} {Ratio}} \right) -} \\\left( {{Background}\mspace{14mu} {Avg}\mspace{14mu} {Ratio}} \right)\end{matrix}}{\begin{matrix}{\left( {{Minimum}\mspace{14mu} {Inhibition}\mspace{14mu} {Ratio}} \right) -} \\\left( {{Background}\mspace{14mu} {Average}\mspace{14mu} {Ratio}} \right)\end{matrix}} \right)*100} \right)}$

Non-linear regression curves were generated to calculate the IC₅₀ anddose-response relationship using triplicate wells per concentration ofcompound.

SMYD3 cell assay data for representative Compounds of the Disclosure arepresented in Tables 1A, 2A, and 3A in the column titled “SMYD3 Cell IC₅₀(μM).”

Example 32 SMYD2 Assay General Materials

S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), bicine,Tween20, dimethylsulfoxide (DMSO), bovine skin gelatin (BSG), andTris(2-carboxyethyl)phosphine hydrochloride (TCEP) were purchased fromSigma-Aldrich at the highest level of purity possible. ³H-SAM waspurchase from American Radiolabeled Chemicals with a specific activityof 80 Ci/mmol. 384-well streptavidin Flashplates were purchased fromPerkinElmer.

Substrates

Peptide was synthesized with a N-terminal linker-affinity tag motif anda C-terminal amide cap by 21^(st) Century Biochemicals. The peptide washigh high-performance liquid chromatography (HPLC) purified to greaterthan 95% purity and confirmed by liquid chromatography mass spectrometry(LC-MS). The sequence was ARTKQTARKSTGGKAPRKQLATKAARKSA(K-Biot)-amide.(SEQ ID NO:3) Production of Recombinant SMYD2 Enzymes for BiochemicalEnzyme Activity Assays

Full length SMYD2 (NP 064582.2) was cloned into a pFastbac-Htb-licvector with an N-terminal His6 tag and FLAG tag, preceded by a TEVprotease cleavage site. The protein was expressed in Sf9 insect cells.Cells were resuspended in lysis buffer (25 mM HEPES-NaOH, pH 7.5, 200 mMNaCl, 5% glycerol, and 5 mM (3-ME) and lysed by sonication. The proteinwas purified by Ni-NTA (Qiagen), followed by TEV cleavage to remove theHis6 tag, subtractive Ni-NTA (Qiagen), and gel filtration chromatographyusing an S200 column (GE Healthcare). Purified protein was stored in 20mM Tris-HCl, pH 8.0, 100 mM NaCl, and 1 mM TCEP.

General Procedure for SMYD2 Enzyme Assays on Peptide Substrates

The assays were all performed in a buffer consisting of 20 mM Bicine(pH=7.6), 1 mM TCEP, 0.005% Bovine Skin Gelatin, and 0.002% Tween20,prepared on the day of use. Compounds in 100% DMSO (1 ul) were spottedinto a polypropylene 384-well V-bottom plates (Greiner) using aPlatemate Plus outfitted with a 384-channel head (Thermo Scientific).DMSO (1 ul) was added to Columns 11, 12, 23, 24, rows A-H for themaximum signal control and 1 ul of SAH, a known product and inhibitor ofSMYD2, was added to columns 11, 12, 23, 24, rows I-P for the minimumsignal control. A cocktail (40 ul) containing the SMYD2 enzyme was addedby Multidrop Combi (Thermo-Fisher). The compounds were allowed toincubate with SMYD2 for 30 min at room temperature, then a cocktail (10ul) containing ³H-SAM and peptide was added to initiate the reaction(final volume=51 ul). The final concentrations of the components were asfollows: SMYD2 was 1.5 nM, ³H-SAM was 10 nM, and peptide was 60 nM, SAHin the minimum signal control wells was 1000 uM, and the DMSOconcentration was 2%. The assays were stopped by the addition ofnon-radioactive SAM (10 ul) to a final concentration of 600 uM, whichdilutes the ³H-SAM to a level where its incorporation into the peptidesubstrate is no longer detectable. 50 ul of the reaction in the 384-wellpolypropylene plate was then transferred to a 384-well Flashplate andthe biotinylated peptides were allowed to bind to the streptavidinsurface for at least 1 hour before being washed three times with 0.1%Tween20 in a Biotek ELx405 plate washer. The plates were then read in aPerkinElmer TopCount plate reader to measure the quantity of ³H-labeledpeptide bound to the Flashplate surface, measured as disintegrations perminute (dpm) or alternatively, referred to as counts per minute (cpm).

% Inhibition Calculation

${\% \mspace{14mu} {inh}} = {100 - {\left( \frac{{dpm}_{cmpd} - {dpm}_{\min}}{{dpm}_{\max} - {dpm}_{\min}} \right) \times 100}}$

Where dpm=disintegrations per minute, cmpd=signal in assay well, and minand max are the respective minimum and maximum signal controls.

Four-Parameter IC50 Fit

${\% \mspace{14mu} {inhibition}} = {{Bottom} + \frac{\left( {{Top} - {Bottom}} \right)}{\left( {1 + \left( {{IC}_{50}{\text{/}\lbrack I\rbrack}} \right)^{{HIll}\mspace{14mu} {coefficient}}} \right)}}$

Where top and bottom are the normally allowed to float, but may be fixedat 100 or 0 respectively in a 3-parameter fit. The Hill Coefficientnormally allowed to float but may also be fixed at 1 in a 3-parameterfit. I is the compound concentration.

Having now fully described this invention, it will be understood bythose of ordinary skill in the art that the same can be performed withina wide and equivalent range of conditions, formulations, and otherparameters without affecting the scope of the invention or anyembodiment thereof.

Other embodiments of the invention will be apparent to those skilled inthe art from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

All patents and publications cited herein are fully incorporated byreference herein in their entirety.

1. A compound having Formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein: B is:

X is selected from the group consisting of —S(═O)₂—, S(═O)₂N(R⁷)—, —S(═O)₂C(R⁸)(H)—, —C(═O)N(R⁷)—, —C(═O)O—, —C(O)C(R⁸)(H)—, and —S(═O)₂N(R⁷)C(═O)N(R¹¹)—; or X is absent; wherein the sulfur atom of —S(═O)₂N(R⁷)—, —S(═O)₂C(R⁸)(H)—, or —S(═O)₂N(R⁷)C(═O)N(R¹¹)— is attached to the nitrogen atom of B, the carbon atom of —C(═O)N(R⁷)— or —C(═O)O— is attached to the nitrogen atom of B, and the carbonyl carbon atom of —C(═O)C(R⁸)(H)— is attached the nitrogen atom of B; Z is selected from the group consisting of hydrogen, optionally substituted C₁₋₆ alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alkyl, [(heterocyclo)alkylamino]alkyl, alkoxyalkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C₃₋₁₂ cycloalkyl, aralkyl, and heteroaralkyl; R¹ is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, and cyclopropyl; R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or R^(2a) and R^(2b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(3a) and R^(3b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(4a) and R^(4b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(5a) and R^(5b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), and R^(4b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; and R^(3a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2a), R^(2b), R^(3b), R^(4a), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(2a) and R^(4a) taken together form a C₁₋₄ bridge; and R^(2b), R^(3a), R^(3b), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(3a) and R^(5a) taken form a C₁₋₄ bridge; and R^(2a), R^(2b), R^(3b), R^(4a), R^(4b), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; R⁶ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; R⁷ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; R⁸ is selected from the group consisting of hydrogen, C₁₋₄ alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and —N(R⁹)C(═O)R¹⁰; R⁹ is selected from the group consisting of hydrogen and C₁₋₄ alkyl; R¹⁰ is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl; and R¹¹ is selected from the group consisting of hydrogen and C₁₋₄ alkyl. with the proviso that said compound having Formula I is not: 5-cyclopropyl-N-(piperidin-4-yl)isoxazole-3-carboxamide; N-(8-azabicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide; N-(1-(2-amino-2-oxoethyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; 5-cyclopropyl-N-(1-(methylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide; N-(1-benzylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; 5-cyclopropyl-N-(1-isobutyrylpiperidin-4-yl)isoxazole-3-carboxamide; N-(1-benzoylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; ethyl 4-(5-cyclopropylisoxazole-3-carboxamido)piperidine-1-carboxylate; 5-cyclopropyl-N-(1-(furan-3-carbonyl)piperidin-4-yl)isoxazole-3-carboxamide; 5-cyclopropyl-N-(1-((4-methoxyphenyl)sulfonyl)piperidin-4-yl)isoxazole-3-carboxamide; 5-cyclopropyl-N-(1-tosylpiperidin-4-yl)isoxazole-3-carboxamide; 5-cyclopropyl-N-(1-(2,6-dimethylpyrimidin-4-yl)piperidin-4-yl)isoxazole-3-carboxamide; N-(1-((4-acetamidophenyl)sulfonyl)piperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide; 5-cyclopropyl-N-(1-(4-isopropyl-5-(pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3-carboxamide; N-(1-(7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)piperidin-4-yl)-5-ethylisoxazole-3-carboxamide; or 5-ethyl-N-(1-(4-isopropyl-5-(pyridin-4-yl)pyrimidin-2-yl)piperidin-4-yl)isoxazole-3-carboxamide.
 2. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:


3. The compound of claim 2, or a pharmaceutically acceptable salt or hydrate thereof, wherein R⁶ is selected from the group consisting of hydrogen and methyl.
 4. The compound of claim 3, or a pharmaceutically acceptable salt or hydrate thereof, wherein R⁶ is hydrogen.
 5. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

and R^(2a) is selected from the group consisting of halo, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl.
 6. The compound of claim 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


7. The compound of claim 6, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) is selected from the group consisting of methyl, ethyl, phenyl, —CH₂Ph, —CF₃, —CO₂Et, and —CH₂OH.
 8. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

and R^(3a) is selected from the group consisting of halo, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl.
 9. The compound of claim 8, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


10. The compound of claim 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and —CH₂Ph.
 11. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

and R^(2a) and R^(2b) are each independently selected from the group consisting of halo and C₁₋₆ alkyl; or R^(2a) and R^(2b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl.
 12. The compound of claim 11, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:

R^(2a) and R^(2b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl.
 13. The compound of claim 11, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


14. The compound of claim 11, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:

and R^(2a) and R^(2b) are each independently selected from the group consisting of halo and C₁₋₄ alkyl.
 15. The compound of claim 14, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) and R^(2b) are selected from the group consisting of fluoro and methyl.
 16. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

R^(3a) and R^(3b) are each independently selected from the group consisting of halo and C₁₋₆ alkyl; or R^(3a) and R^(3b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl.
 17. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:

and R^(3a) and R^(3b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl.
 18. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


19. The compound of claim 16, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:

and R^(3a) and R^(3b) are each independently selected from the group consisting of halo and C₁₋₄ alkyl.
 20. The compound of claim 19, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) and R^(3b) are selected from the group consisting of fluoro and methyl.
 21. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

R^(3a) and R^(5a) are each independently C₁₋₆ alkyl; or R^(3a) and R^(5a) taken together form a C₁₋₄ bridge.
 22. The compound of claim 21, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


23. The compound of claim 22, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) and R^(5a) are each independently C₁₋₄ alkyl.
 24. The compound of claim 23, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) and R^(5a) are each methyl or ethyl.
 25. The compound of claim 21, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:


26. The compound of claim 25, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


27. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

wherein R^(2a) and R^(3a) are each independently C₁₋₆ alkyl.
 28. The compound of claim 27, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:


29. The compound of claim 28, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) and R^(3a) are each independently C₁₋₄ alkyl.
 30. The compound of claim 29, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) and R^(3a) are each methyl or ethyl.
 31. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

wherein R^(3a) and R^(4a) are each independently C₁₋₆ alkyl; or R^(3a) and R^(4a) taken together form a C₁₋₄ bridge.
 32. The compound of claim 31, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:


33. The compound of claim 32 or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) and R^(4a) are each independently C₁₋₄ alkyl.
 34. The compound of claim 33, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(3a) and R^(4a) are each methyl or ethyl.
 35. The compound of claim 34, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


36. The compound of claim 35, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


37. The compound of claim 35, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is selected from the group consisting of:


38. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:

wherein R^(2a) and R^(5a) are each independently selected from the group consisting of C₁₋₆ alkyl and alkoxycarbonyl; or R^(2a) and R^(5a) taken together form a C₁₋₄ bridge.
 39. The compound of claim 38, or a pharmaceutically acceptable salt or hydrate thereof, wherein B is:


40. The compound of claim 39, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) and R^(5a) are each independently selected from the group consisting of C₁₋₄ alkyl and alkoxycarbonyl.
 41. The compound of claim 40, or a pharmaceutically acceptable salt or hydrate thereof, wherein R^(2a) and R^(5a) are each independently selected from the group consisting of methyl and —CO₂Me.
 42. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —S(═O)₂—.
 43. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —C(═O)—.
 44. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is absent.
 45. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —S(═O)₂N(H)—.
 46. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —C(═O)N(H)—.
 47. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —C(═O)O—.
 48. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —S(═O)₂CH₂—.
 49. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is —C(═O)CH₂—.
 50. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is selected from the group consisting of:

and R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and —N(R⁹)C(═O)R¹⁰.
 51. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein X is selected from the group consisting of:

and R⁸ is selected from the group consisting of C₁₋₄ alkyl, amino, alkylamino, dialkylamino, cycloalkylamino, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, hydroxyalkyl, and —N(R⁹)C(═O)R¹⁰.
 52. The compound of claim 51, or a pharmaceutically acceptable salt or hydrate thereof, wherein R⁸ is selected from the group consisting of —NH₂, —CH₂NH₂, and —N(H)C(═O)R¹⁰.
 53. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C₆₋₁₄ aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and optionally substituted C₃₋₁₂ cycloalkyl.
 54. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein one or more of R^(2a), R^(3a), R^(4a), and R^(5a) is independently selected from the group consisting of halo, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl.
 55. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein R⁶ is C₁₋₄ alkyl.
 56. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein: R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, C₁₋₆ alkyl, C₃₋₁₂ cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C₆₋₁₄ aryl, aralkyl, and alkoxycarbonyl; or R^(2a) and R^(2b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(3a), R^(3b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(3a) and R^(3b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(4a), R^(4b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(4a) and R^(4b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b), R^(5a), and R^(5b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl; or R^(5a) and R^(5b) taken together with the carbon atom to which they are attached form a C₃₋₆ cycloalkyl; and R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), and R^(4b) are each independently selected from the group consisting of hydrogen, halo, and C₁₋₄ alkyl.
 57. The compound of claim 1 having Formula III:

or a pharmaceutically acceptable salt or hydrate thereof.
 58. The compound of claim 1 having Formula IV:

or a pharmaceutically acceptable salt or hydrate thereof.
 59. The compound of claim 1 having Formula V:

or a pharmaceutically acceptable salt or hydrate thereof.
 60. The compound of claim 1 having Formula VI:

or a pharmaceutically acceptable salt or hydrate thereof.
 61. The compound of claim 1 having Formula VII:

or a pharmaceutically acceptable salt or hydrate thereof.
 62. The compound of claim 1 having Formula VIII:

or a pharmaceutically acceptable salt or hydrate thereof.
 63. The compound of claim 1 having Formula IX:

or a pharmaceutically acceptable salt or hydrate thereof.
 64. The compound of claim 1 having Formula X:

or a pharmaceutically acceptable salt or hydrate thereof.
 65. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein R¹ is ethyl.
 66. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein R¹ is cyclopropyl.
 67. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C₆₋₁₄ aryl, and optionally substituted 4- to 14-membered heterocyclo.
 68. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-substituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
 69. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is (heterocyclo)alkyl.
 70. The compound of claim 69, or a pharmaceutically acceptable salt or hydrate thereof, wherein said (heterocyclo)alkyl is:

and R¹² is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
 71. The compound of claim 70, or a pharmaceutically acceptable salt or hydrate thereof, wherein R¹² is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl
 72. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein Z is selected from the group consisting of:


73. The compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, selected from any one or more of the compounds provided in Table 1, Table 1A, Table 2, Table 2A, Table 3, or Table 3A of the specification.
 74. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
 75. A method of treating a patient comprising administering to the patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, wherein the patient has cancer.
 76. The method of claim 75, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor. 77-82. (canceled)
 83. A kit comprising the compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt or hydrate thereof, to a patient having cancer.
 84. The kit of claim 83, wherein the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, preimary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma periotonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Warthin's tumor, and Wilms' tumor.
 85. A method of treating a SMYD protein mediated disorder comprising administering to a subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt or hydrate thereof in an effective amount to treat the SMYD protein mediated disorder. 